bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Three-Year Interval for the Multi-Target Stool DNA Test for Colorectal Cancer Screening: A Longitudinal Study
Authors: Imperiale Thomas F. , Lavin Philip T. , Marti Tara N. , Jakubowski Debbie , Itzkowitz Steven H. , May Folasade P. , Limburg Paul J. , Sweetser Seth , Daghestani Anas , Berger Barry M.
Published: March 2024

Abstract
Data supporting the clinical utility of multi-target stool DNA (mt-sDNA) at the guideline-recommended 3-year interval have not been reported.

Between April 2015 and July 2016, candidates for colorectal cancer screening whose providers prescribed the mt-sDNA test were enrolled. Participants with a positive baseline test were recommended for colonoscopy and completed the study. Those with a negative baseline test were followed annually for 3 years. In year 3, the mt-sDNA test was repeated and colonoscopy was recommended independent of results. Data were analyzed using the Predictive Summary Index (PSI), a measure of the gain in certainty for dichotomous diagnostic tests (where a positive value indicates a net gain), and by comparing observed versus expected colorectal cancers and advanced precancerous lesions.

Of 2,404 enrolled subjects, 2,044 (85%) had a valid baseline mt-sDNA result [284 (13.9%) positive and 1,760 (86.1%) negative]. Following participant attrition, the year 3 intention to screen cohort included 591 of 1,760 (33.6%) subjects with valid mt-sDNA and colonoscopy results, with no colorectal cancers and 63 advanced precancerous lesions [22 (34.9%) detected by mt-sDNA] and respective PSI values of 0% (P = 1) and 9.3% (P = 0.01). The observed 3-year colorectal cancer yield was lower than expected (one-sided P = 0.09), while that for advanced precancerous lesions was higher than expected (two-sided P = 0.009).

Repeat mt-sDNA screening at a 3-year interval resulted in a statistically significant gain in detection of advanced precancerous lesions. Due to absence of year 3 colorectal cancers, the PSI estimate for colorectal cancer was underpowered and could not be reliably quantified. Larger studies are required to assess the colorectal cancer study findings.
Prevention Relevance:
Understanding the 3-year yield of mt-sDNA for colorectal cancer and advanced precancerous polyps is required to ensure the clinical appropriateness of the 3-year interval and to optimize mt-sDNA's screening effectiveness.
Data from HER2 Amplification: A Potential Mechanism of Acquired Resistance to EGFR Inhibition in EGFR-Mutant Lung Cancers That Lack the Second-Site EGFRT790M Mutation
Authors: Takezawa Ken , Pirazzoli Valentina , Arcila Maria E. , Nebhan Caroline A. , Song Xiaoling , de Stanchina Elisa , Ohashi Kadoaki , Janjigian Yelena Y. , Spitzler Paula J. , Melnick Mary Ann , Riely Greg J. , Kris Mark G. , Miller Vincent A. , Ladanyi Marc , Politi Katerina , Pao William
Published: March 2024

Abstract
EGF receptor (EGFR)–mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Because afatinib is also a potent HER2 inhibitor, we investigated the role of HER2 in EGFR-mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. FISH analysis revealed that HER2 was amplified in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplification and EGFRT790M were mutually exclusive. Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR-TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR-mutant tumors with acquired resistance to EGFR-TKIs.

Significance: Because all EGFR-mutant lung adenocarcinomas eventually develop resistance to TKI therapy, understanding mechanisms of acquired resistance may improve clinical outcomes. These results implicate HER2 as a novel protein involved in the sensitivity or resistance of EGFR-mutant lung cancer and provide a rationale to assess the status of and possibly target HER2 in such tumors. Cancer Discov; 2(10); 922–33. ©2012 AACR.

Read the Commentary on this article by Blakely and Bivona, p. 872.

This article is highlighted in the In This Issue feature, p. 857.
Data from Cancer-Specific Requirement for BUB1B/BUBR1 in Human Brain Tumor Isolates and Genetically Transformed Cells
Authors: Ding Yu , Hubert Christopher G. , Herman Jacob , Corrin Philip , Toledo Chad M. , Skutt-Kakaria Kyobi , Vazquez Julio , Basom Ryan , Zhang Bin , Risler Jennifer K. , Pollard Steven M. , Nam Do-Hyun , Delrow Jeffery J. , Zhu Jun , Lee Jeongwu , DeLuca Jennifer , Olson James M. , Paddison Patrick J.
Published: March 2024

Abstract
To identify new candidate therapeutic targets for glioblastoma multiforme, we combined functional genetics and glioblastoma network modeling to identify kinases required for the growth of patient-derived brain tumor–initiating cells (BTIC) but that are dispensable to proliferating human neural stem cells (NSC). This approach yielded BUB1B/BUBR1, a critical mitotic spindle checkpoint player, as the top-scoring glioblastoma lethal kinase. Knockdown of BUB1B inhibited expansion of BTIC isolates, both in vitro and in vivo, without affecting proliferation of NSCs or astrocytes. Mechanistic studies revealed that BUB1B's GLE2p-binding sequence (GLEBS) domain activity is required to suppress lethal kinetochore–microtubule (KT–MT) attachment defects in glioblastoma isolates and genetically transformed cells with altered sister KT dynamics, which likely favor KT–MT instability. These results indicate that glioblastoma tumors have an added requirement for BUB1B to suppress lethal consequences of altered KT function and further suggest that sister KT measurements may predict cancer-specific sensitivity to BUB1B inhibition and perhaps other mitotic targets that affect KT–MT stability.

Significance: Currently, no effective therapies are available for glioblastoma, the most frequent and aggressive brain tumor. Our results suggest that targeting the GLEBS domain activity of BUB1B may provide a therapeutic window for glioblastoma, as the GLEBS domain is nonessential in untransformed cells. Moreover, the results further suggest that sister KT distances at metaphase may predict sensitivity to anticancer therapeutics targeting KT function. Cancer Discov; 3(2); 198–211. ©2012 AACR.

See related commentary by Venere et al., p. 141

This article is highlighted in the In This Issue feature, p. 125
Data from Characterization of KRAS Rearrangements in Metastatic Prostate Cancer
Authors: Wang Xiao-Song , Shankar Sunita , Dhanasekaran Saravana M. , Ateeq Bushra , Sasaki Atsuo T. , Jing Xiaojun , Robinson Daniel , Cao Qi , Prensner John R. , Yocum Anastasia K. , Wang Rui , Fries Daniel F. , Han Bo , Asangani Irfan A. , Cao Xuhong , Li Yong , Omenn Gilbert S. , Pflueger Dorothee , Gopalan Anuradha , Reuter Victor E. , Kahoud Emily Rose , Cantley Lewis C. , Rubin Mark A. , Palanisamy Nallasivam , Varambally Sooryanarayana , Chinnaiyan Arul M.
Published: March 2024

Abstract
Using an integrative genomics approach called amplification breakpoint ranking and assembly analysis, we nominated KRAS as a gene fusion with the ubiquitin-conjugating enzyme UBE2L3 in the DU145 cell line, originally derived from prostate cancer metastasis to the brain. Interestingly, analysis of tissues revealed that 2 of 62 metastatic prostate cancers harbored aberrations at the KRAS locus. In DU145 cells, UBE2L3-KRAS produces a fusion protein, a specific knockdown of which attenuates cell invasion and xenograft growth. Ectopic expression of the UBE2L3-KRAS fusion protein exhibits transforming activity in NIH 3T3 fibroblasts and RWPE prostate epithelial cells in vitro and in vivo. In NIH 3T3 cells, UBE2L3-KRAS attenuates MEK/ERK signaling, commonly engaged by oncogenic mutant KRAS, and instead signals via AKT and p38 mitogen-activated protein kinase (MAPK) pathways. This is the first report of a gene fusion involving the Ras family, suggesting that this aberration may drive metastatic progression in a rare subset of prostate cancers.

Significance: This is the first description of an oncogenic gene fusion of KRAS, one of the most studied proto-oncogenes. KRAS rearrangement may represent the driving mutation in a rare subset of metastatic prostate cancers, emphasizing the importance of RAS-RAF-MAPK signaling in this disease. Cancer Discovery; 1(1); 35–43. © 2011 AACR.

Read the Commentary on this article by Edgren et al., p. 12

This article is highlighted in the In This Issue feature, p. 4
Data from Outlier Kinase Expression by RNA Sequencing as Targets for Precision Therapy
Authors: Kothari Vishal , Wei Iris , Shankar Sunita , Kalyana-Sundaram Shanker , Wang Lidong , Ma Linda W. , Vats Pankaj , Grasso Catherine S. , Robinson Dan R. , Wu Yi-Mi , Cao Xuhong , Simeone Diane M. , Chinnaiyan Arul M. , Kumar-Sinha Chandan
Published: March 2024

Abstract
Protein kinases represent the most effective class of therapeutic targets in cancer; therefore, determination of kinase aberrations is a major focus of cancer genomic studies. Here, we analyzed transcriptome sequencing data from a compendium of 482 cancer and benign samples from 25 different tissue types, and defined distinct “outlier kinases” in individual breast and pancreatic cancer samples, based on highest levels of absolute and differential expression. Frequent outlier kinases in breast cancer included therapeutic targets like ERBB2 and FGFR4, distinct from MET, AKT2, and PLK2 in pancreatic cancer. Outlier kinases imparted sample-specific dependencies in various cell lines, as tested by siRNA knockdown and/or pharmacologic inhibition. Outlier expression of polo-like kinases was observed in a subset of KRAS-dependent pancreatic cancer cell lines, and conferred increased sensitivity to the pan-PLK inhibitor BI-6727. Our results suggest that outlier kinases represent effective precision therapeutic targets that are readily identifiable through RNA sequencing of tumors.

Significance: Various breast and pancreatic cancer cell lines display sensitivity to knockdown or pharmacologic inhibition of sample-specific outlier kinases identified by high-throughput transcriptome sequencing. Outlier kinases represent personalized therapeutic targets that could improve combinatorial therapy options. Cancer Discov; 3(3); 280–93. ©2013 AACR.

See related commentary by Yegnasubramanian and Maitra, p. 252

This article is highlighted in the In This Issue feature, p. 239
Data from Relief of Feedback Inhibition of HER3 Transcription by RAF and MEK Inhibitors Attenuates Their Antitumor Effects in BRAF-Mutant Thyroid Carcinomas
Authors: Montero-Conde Cristina , Ruiz-Llorente Sergio , Dominguez Jose M. , Knauf Jeffrey A. , Viale Agnes , Sherman Eric J. , Ryder Mabel , Ghossein Ronald A. , Rosen Neal , Fagin James A.
Published: March 2024

Abstract
The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF-mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. In contrast to melanomas, inhibition of mitogen-activated protein kinase (MAPK) signaling by PLX4032 is transient in thyroid and colorectal cancer cells. The rebound in extracellular signal-regulated kinase (ERK) in thyroid cells is accompanied by increased HER3 signaling caused by induction of ERBB3 (HER3) transcription through decreased promoter occupancy by the transcriptional repressors C-terminal binding protein 1 and 2 and by autocrine secretion of neuregulin-1 (NRG1). The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF-mutant thyroid cancer cells to RAF or MAP-ERK kinase inhibitors. This provides a rationale for combining ERK pathway antagonists with inhibitors of feedback-reactivated HER signaling in this disease. The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of specific receptor tyrosine kinases, and the abundance of their respective ligands.

Significance: Thyroid cancer cell lines with mutant BRAF are resistant to PLX4032. RAF inhibitors transiently inhibit the ERK pathway and de-repress HER3 transcription. In the context of constitutive NRG1 secretion, this results in an ERK and AKT rebound that diminishes the antitumor effects of RAF inhibitors, which is overcome by combination with lapatinib. Cancer Discov; 3(5); 520–33. ©2013 AACR.

See related commentary by Girotti and Marais, p. 487

This article is highlighted in the In This Issue feature, p. 471
Data from Promotion of Colorectal Cancer Invasion and Metastasis through Activation of NOTCH–DAB1–ABL–RHOGEF Protein TRIO
Authors: Sonoshita Masahiro , Itatani Yoshiro , Kakizaki Fumihiko , Sakimura Kenji , Terashima Toshio , Katsuyama Yu , Sakai Yoshiharu , Taketo M. Mark
Published: March 2024

Abstract
We have recently identified a metastasis suppressor gene for colorectal cancer: AES/Aes, which encodes an endogenous inhibitor of NOTCH signaling. When Aes is knocked out in the adenomatous epithelium of intestinal polyposis mice, their tumors become malignant, showing marked submucosal invasion and intravasation. Here, we show that one of the genes induced by NOTCH signaling in colorectal cancer is DAB1/Dab1. Genetic depletion of DAB1 suppresses cancer invasion and metastasis in the NOTCH signaling–activated mice. DAB1 is phosphorylated by ABL tyrosine kinase, which activates ABL reciprocally. Consistently, inhibition of ABL suppresses cancer invasion in mice. Furthermore, we show that one of the targets of ABL is the RAC/RHOGEF protein TRIO, and that phosphorylation at its Tyr residue 2681 (pY2681) causes RHO activation in colorectal cancer cells. Its unphosphorylatable mutation TRIO Y2681F reduces RHOGEF activity and inhibits invasion of colorectal cancer cells. Importantly, TRIO pY2681 correlates with significantly poorer prognosis of patients with colorectal cancer after surgery.

Significance: These results indicate that TRIO pY2681 is one of the downstream effectors of NOTCH signaling activation in colorectal cancer, and can be a prognostic marker, helping to determine the therapeutic modality of patients with colorectal cancer. Cancer Discov; 5(2); 198–211. ©2014 AACR.

See related commentary by Kranenburg, p. 115

This article is highlighted in the In This Issue feature, p. 97
Data from Polyclonal Secondary FGFR2 Mutations Drive Acquired Resistance to FGFR Inhibition in Patients with FGFR2 Fusion–Positive Cholangiocarcinoma
Authors: Goyal Lipika , Saha Supriya K. , Liu Leah Y. , Siravegna Giulia , Leshchiner Ignaty , Ahronian Leanne G. , Lennerz Jochen K. , Vu Phuong , Deshpande Vikram , Kambadakone Avinash , Mussolin Benedetta , Reyes Stephanie , Henderson Laura , Sun Jiaoyuan Elisabeth , Van Seventer Emily E. , Gurski Joseph M. , Baltschukat Sabrina , Schacher-Engstler Barbara , Barys Louise , Stamm Christelle , Furet Pascal , Ryan David P. , Stone James R. , Iafrate A. John , Getz Gad , Porta Diana Graus , Tiedt Ralph , Bardelli Alberto , Juric Dejan , Corcoran Ryan B. , Bardeesy Nabeel , Zhu Andrew X.
Published: March 2024

Abstract
Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion–positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intralesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies.

Significance: We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion–positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target. Cancer Discov; 7(3); 252–63. ©2016 AACR.

See related commentary by Smyth et al., p. 248.

This article is highlighted in the In This Issue feature, p. 235
Data from MYC Drives a Subset of High-Risk Pediatric Neuroblastomas and Is Activated through Mechanisms Including Enhancer Hijacking and Focal Enhancer Amplification
Authors: Zimmerman Mark W. , Liu Yu , He Shuning , Durbin Adam D. , Abraham Brian J. , Easton John , Shao Ying , Xu Beisi , Zhu Shizhen , Zhang Xiaoling , Li Zhaodong , Weichert-Leahey Nina , Young Richard A. , Zhang Jinghui , Look A. Thomas
Published: March 2024

Abstract
The amplified MYCN gene serves as an oncogenic driver in approximately 20% of high-risk pediatric neuroblastomas. Here, we show that the family member MYC is a potent transforming gene in a separate subset of high-risk neuroblastoma cases (∼10%), based on (i) its upregulation by focal enhancer amplification or genomic rearrangements leading to enhancer hijacking, and (ii) its ability to transform neuroblastoma precursor cells in a transgenic animal model. The aberrant regulatory elements associated with oncogenic MYC activation include focally amplified distal enhancers and translocation of highly active enhancers from other genes to within topologically associating domains containing the MYC gene locus. The clinical outcome for patients with high levels of MYC expression is virtually identical to that of patients with amplification of the MYCN gene, a known high-risk feature of this disease. Together, these findings establish MYC as a bona fide oncogene in a clinically significant group of high-risk childhood neuroblastomas.

Significance: Amplification of the MYCN oncogene is a recognized hallmark of high-risk pediatric neuroblastoma. Here, we demonstrate that MYC is also activated as a potent oncogene in a distinct subset of neuroblastoma cases through either focal amplification of distal enhancers or enhancer hijacking mediated by chromosomal translocation. Cancer Discov; 8(3); 320–35. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 253
Data from Colorectal Tumors Require NUAK1 for Protection from Oxidative Stress
Authors: Port Jennifer , Muthalagu Nathiya , Raja Meera , Ceteci Fatih , Monteverde Tiziana , Kruspig Björn , Hedley Ann , Kalna Gabriela , Lilla Sergio , Neilson Lisa , Brucoli Martina , Gyuraszova Katarina , Tait-Mulder Jacqueline , Mezna Mokdad , Svambaryte Silvija , Bryson Amy , Sumpton David , McVie Allan , Nixon Colin , Drysdale Martin , Esumi Hiroyasu , Murray Graeme I. , Sansom Owen J. , Zanivan Sara R. , Murphy Daniel J.
Published: March 2024

Abstract
Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human cancer, and antioxidant defenses are implicated in resistance to chemotherapy and radiotherapy. Targeted suppression of antioxidant defenses could thus broadly improve therapeutic outcomes. Here, we identify the AMPK-related kinase NUAK1 as a key component of the antioxidant stress response pathway and reveal a specific requirement for this role of NUAK1 in colorectal cancer. We show that NUAK1 is activated by oxidative stress and that this activation is required to facilitate nuclear import of the antioxidant master regulator NRF2: Activation of NUAK1 coordinates PP1β inhibition with AKT activation in order to suppress GSK3β-dependent inhibition of NRF2 nuclear import. Deletion of NUAK1 suppresses formation of colorectal tumors, whereas acute depletion of NUAK1 induces regression of preexisting autochthonous tumors. Importantly, elevated expression of NUAK1 in human colorectal cancer is associated with more aggressive disease and reduced overall survival.

Significance: This work identifies NUAK1 as a key facilitator of the adaptive antioxidant response that is associated with aggressive disease and worse outcome in human colorectal cancer. Our data suggest that transient NUAK1 inhibition may provide a safe and effective means for treatment of human colorectal cancer via disruption of intrinsic antioxidant defenses. Cancer Discov; 8(5); 632–47. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 517
Data from Identification of Pik3ca Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Pten Loss to Accelerate Progression and Castration-Resistant Growth
Authors: Pearson Helen B. , Li Jason , Meniel Valerie S. , Fennell Christina M. , Waring Paul , Montgomery Karen G. , Rebello Richard J. , Macpherson Arthi A. , Koushyar Sarah , Furic Luc , Cullinane Carleen , Clarkson Richard W. , Smalley Matthew J. , Simpson Kaylene J. , Phesse Toby J. , Shepherd Peter R. , Humbert Patrick O. , Sansom Owen J. , Phillips Wayne A.
Published: March 2024

Abstract
Genetic alterations that potentiate PI3K signaling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report PIK3CA mutation/amplification correlates with poor survival of patients with prostate cancer. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate Pik3ca in mouse prostate epithelium. We show Pik3caH1047R mutation causes p110α-dependent invasive prostate carcinoma in vivo. Furthermore, we report that PIK3CA mutation and PTEN loss coexist in patients with prostate cancer and can cooperate in vivo to accelerate disease progression via AKT–mTORC1/2 hyperactivation. Contrasting single mutants that slowly acquire castration-resistant prostate cancer (CRPC), concomitant Pik3ca mutation and Pten loss caused de novo CRPC. Thus, Pik3ca mutation and Pten deletion are not functionally redundant. Our findings indicate that PIK3CA mutation is an attractive prognostic indicator for prostate cancer that may cooperate with PTEN loss to facilitate CRPC in patients.

Significance: We show PIK3CA mutation correlates with poor prostate cancer prognosis and causes prostate cancer in mice. Moreover, PIK3CA mutation and PTEN loss coexist in prostate cancer and can cooperate in vivo to accelerate tumorigenesis and facilitate CRPC. Delineating this synergistic relationship may present new therapeutic/prognostic approaches to overcome castration/PI3K–AKT–mTORC1/2 inhibitor resistance. Cancer Discov; 8(6); 764–79. ©2018 AACR.

See related commentary by Triscott and Rubin, p. 682.

This article is highlighted in the In This Issue feature, p. 663
Data from Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion
Authors: Piotrowska Zofia , Isozaki Hideko , Lennerz Jochen K. , Gainor Justin F. , Lennes Inga T. , Zhu Viola W. , Marcoux Nicolas , Banwait Mandeep K. , Digumarthy Subba R. , Su Wenjia , Yoda Satoshi , Riley Amanda K. , Nangia Varuna , Lin Jessica J. , Nagy Rebecca J. , Lanman Richard B. , Dias-Santagata Dora , Mino-Kenudson Mari , Iafrate A. John , Heist Rebecca S. , Shaw Alice T. , Evans Erica K. , Clifford Corinne , Ou Sai-Hong I. , Wolf Beni , Hata Aaron N. , Sequist Lecia V.
Published: March 2024

Abstract
We present a cohort of 41 patients with osimertinib resistance biopsies, including 2 with an acquired CCDC6–RET fusion. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of RET fusions in an EGFR-mutant cancer, we expressed CCDC6–RET in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells and found that CCDC6–RET was sufficient to confer resistance to EGFR tyrosine kinase inhibitors (TKI). The selective RET inhibitors BLU-667 and cabozantinib resensitized CCDC6–RET-expressing cells to EGFR inhibition. Finally, we treated 2 patients with EGFR-mutant NSCLC and RET-mediated resistance with osimertinib and BLU-667. The combination was well tolerated and led to rapid radiographic response in both patients. This study provides proof of concept that RET fusions can mediate acquired resistance to EGFR TKIs and that combined EGFR and RET inhibition with osimertinib/BLU-667 may be a well-tolerated and effective treatment strategy for such patients.
Significance:
The role of RET fusions in resistant EGFR-mutant cancers is unknown. We report that RET fusions mediate resistance to EGFR inhibitors and demonstrate that this bypass track can be effectively targeted with a selective RET inhibitor (BLU-667) in the clinic.

This article is highlighted in the In This Issue feature, p. 1494
Data from The Landscape of Human Cancer Proteins Targeted by SARS-CoV-2
Authors: Tutuncuoglu Beril , Cakir Merve , Batra Jyoti , Bouhaddou Mehdi , Eckhardt Manon , Gordon David E. , Krogan Nevan J.
Published: March 2024

AbstractSummary:
The mapping of SARS-CoV-2 human protein–protein interactions by Gordon and colleagues revealed druggable targets that are hijacked by the virus. Here, we highlight several oncogenic pathways identified at the host–virus interface of SARS-CoV-2 to enable cancer biologists to apply their knowledge for rapid drug repurposing to treat COVID-19, and help inform the response to potential long-term complications of the disease.
Data from Transcription-Associated Cyclin-Dependent Kinases as Targets and Biomarkers for Cancer Therapy
Authors: Chou Jonathan , Quigley David A. , Robinson Troy M. , Feng Felix Y. , Ashworth Alan
Published: March 2024

Abstract
Drugs targeting the cell cycle–regulatory cyclin-dependent kinase (CDK) 4 and 6 have been approved for the treatment of hormone receptor–positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Another class of CDKs, the transcription-associated CDKs, including CDK7, CDK8, CDK9, CDK12 and CDK13, are critical regulators of gene expression. Recent evidence suggests several novel functions of these CDKs, including regulation of epigenetic modifications, intronic polyadenylation, DNA-damage responses, and genomic stability. Here, we summarize our current understanding of the transcriptional CDKs, their utility as biomarkers, and their potential as therapeutic targets.
Significance:
CDK inhibitors targeting CDK4 and CDK6 have been approved in hormone receptor–positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Several studies now point to potential therapeutic opportunities by inhibiting the transcription-associated CDKs as well as therapeutic vulnerabilities with PARP inhibitors and immunotherapy in tumors deficient in these CDKs.
Data from The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies
Authors: Su Angela , Ling Frank , Vaganay Camille , Sodaro Gaetano , Benaksas Chaïma , Dal Bello Reinaldo , Forget Antoine , Pardieu Bryann , Lin Kevin H. , Rutter Justine C. , Bassil Christopher F. , Fortin Gael , Pasanisi Justine , Antony-Debré Iléana , Alexe Gabriela , Benoist Jean-François , Pruvost Alain , Pikman Yana , Qi Jun , Schlageter Marie-Hélène , Micol Jean-Baptiste , Roti Giovanni , Cluzeau Thomas , Dombret Hervé , Preudhomme Claude , Fenouille Nina , Benajiba Lina , Golan Hava M. , Stegmaier Kimberly , Lobry Camille , Wood Kris C. , Itzykson Raphael , Puissant Alexandre
Published: March 2024

Abstract
Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid–related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme MTHFR, which exhibits reduced-function polymorphisms in about 10% of Caucasians, induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Furthermore, this effect is abrogated by supplementation with the MTHFR enzymatic product CH3-THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies.
Significance:
Although MYC-targeting therapies represent a promising strategy for cancer treatment, evidence of predictors of sensitivity to these agents is limited. We pinpoint that folate cycle disturbance and frequent polymorphisms associated with reduced MTHFR activity promote resistance to BET inhibitors. CH3-THF supplementation thus represents a low-risk intervention to enhance their effects.

See related commentary by Marando and Huntly, p. 1791.

This article is highlighted in the In This Issue feature, p. 1775
Data from Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System
Authors: Mehta Vikas , Goel Sanjay , Kabarriti Rafi , Cole Daniel , Goldfinger Mendel , Acuna-Villaorduna Ana , Pradhan Kith , Thota Raja , Reissman Stan , Sparano Joseph A. , Gartrell Benjamin A. , Smith Richard V. , Ohri Nitin , Garg Madhur , Racine Andrew D. , Kalnicki Shalom , Perez-Soler Roman , Halmos Balazs , Verma Amit
Published: March 2024

Abstract
Patients with cancer are presumed to be at increased risk from COVID-19 infection–related fatality due to underlying malignancy, treatment-related immunosuppression, or increased comorbidities. A total of 218 COVID-19–positive patients from March 18, 2020, to April 8, 2020, with a malignant diagnosis were identified. A total of 61 (28%) patients with cancer died from COVID-19 with a case fatality rate (CFR) of 37% (20/54) for hematologic malignancies and 25% (41/164) for solid malignancies. Six of 11 (55%) patients with lung cancer died from COVID-19 disease. Increased mortality was significantly associated with older age, multiple comorbidities, need for ICU support, and elevated levels of D-dimer, lactate dehydrogenase, and lactate in multivariate analysis. Age-adjusted CFRs in patients with cancer compared with noncancer patients at our institution and New York City reported a significant increase in case fatality for patients with cancer. These data suggest the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population.
Significance:
COVID-19 in patients with cancer is associated with a significantly increased risk of case fatality, suggesting the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population.

This article is highlighted in the In This Issue feature, p. 890
Data from Histone Lysine Methylation Dynamics Control EGFR DNA Copy-Number Amplification
Authors: Clarke Thomas L. , Tang Ran , Chakraborty Damayanti , Van Rechem Capucine , Ji Fei , Mishra Sweta , Ma Anqi , Kaniskan H. Ümit , Jin Jian , Lawrence Michael S. , Sadreyev Ruslan I. , Whetstine Johnathan R.
Published: March 2024

Abstract
Acquired chromosomal DNA copy gains are a feature of many tumors; however, the mechanisms that underpin oncogene amplification are poorly understood. Recent studies have begun to uncover the importance of epigenetic states and histone lysine methyltransferases (KMT) and demethylases (KDM) in regulating transient site-specific DNA copy-number gains (TSSG). In this study, we reveal a critical interplay between a myriad of lysine methyltransferases and demethylases in modulating H3K4/9/27 methylation balance to control extrachromosomal amplification of the EGFR oncogene. This study further establishes that cellular signals (hypoxia and EGF) are able to directly promote EGFR amplification through modulation of the enzymes controlling EGFR copy gains. Moreover, we demonstrate that chemical inhibitors targeting specific KMTs and KDMs are able to promote or block extrachromosomal EGFR amplification, which identifies potential therapeutic strategies for controlling EGFR copy-number heterogeneity in cancer, and, in turn, drug response.
Significance:
This study identifies a network of epigenetic factors and cellular signals that directly control EGFR DNA amplification. We demonstrate that chemical inhibitors targeting enzymes controlling this amplification can be used to rheostat EGFR copy number, which uncovers therapeutic opportunities for controlling EGFR DNA amplification heterogeneity and the associated drug response.

This article is highlighted in the In This Issue feature, p. 161
Data from BI-3406, a Potent and Selective SOS1–KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition
Authors: Hofmann Marco H. , Gmachl Michael , Ramharter Juergen , Savarese Fabio , Gerlach Daniel , Marszalek Joseph R. , Sanderson Michael P. , Kessler Dirk , Trapani Francesca , Arnhof Heribert , Rumpel Klaus , Botesteanu Dana-Adriana , Ettmayer Peter , Gerstberger Thomas , Kofink Christiane , Wunberg Tobias , Zoephel Andreas , Fu Szu-Chin , Teh Jessica L. , Böttcher Jark , Pototschnig Nikolai , Schachinger Franziska , Schipany Katharina , Lieb Simone , Vellano Christopher P. , O'Connell Jonathan C. , Mendes Rachel L. , Moll Jurgen , Petronczki Mark , Heffernan Timothy P. , Pearson Mark , McConnell Darryl B. , Kraut Norbert
Published: March 2024

Abstract
KRAS is the most frequently mutated driver of pancreatic, colorectal, and non–small cell lung cancers. Direct KRAS blockade has proved challenging, and inhibition of a key downstream effector pathway, the RAF–MEK–ERK cascade, has shown limited success because of activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective, and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1, thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors.
Significance:
To date, there are no effective targeted pan-KRAS therapies. In-depth characterization of BI-3406 activity and identification of MEK inhibitors as effective combination partners provide an attractive therapeutic concept for the majority of KRAS-mutant cancers, including those fueled by the most prevalent mutant KRAS oncoproteins, G12D, G12V, G12C, and G13D.

See related commentary by Zhao et al., p. 17.

This article is highlighted in the In This Issue feature, p. 1
Data from Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer
Authors: Kieffer Yann , Hocine Hocine R. , Gentric Géraldine , Pelon Floriane , Bernard Charles , Bourachot Brigitte , Lameiras Sonia , Albergante Luca , Bonneau Claire , Guyard Alice , Tarte Karin , Zinovyev Andrei , Baulande Sylvain , Zalcman Gerard , Vincent-Salomon Anne , Mechta-Grigoriou Fatima
Published: March 2024

Abstract
A subset of cancer-associated fibroblasts (FAP+/CAF-S1) mediates immunosuppression in breast cancers, but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19,000 single CAF-S1 fibroblasts from breast cancer. We validate the five most abundant clusters by flow cytometry and in silico analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extracellular matrix proteins and TGFβ signaling, respectively, are indicative of primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 and CTLA4 protein levels in regulatory T lymphocytes (Tregs), which, in turn, increases CAF-S1 cluster 3/TGFβ-myCAF cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance.
Significance:
Our work provides a significant advance in characterizing and understanding FAP+ CAF in cancer. We reached a high resolution at single-cell level, which enabled us to identify specific clusters associated with immunosuppression and immunotherapy resistance. Identification of cluster-specific signatures paves the way for therapeutic options in combination with immunotherapies.

This article is highlighted in the In This Issue feature, p. 1241
Data from EZH2-Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress
Authors: León Theresa E. , Rapoz-D'Silva Tanya , Bertoli Cosetta , Rahman Sunniyat , Magnussen Michael , Philip Brian , Farah Nadine , Richardson Simon E. , Ahrabi Sara , Guerra-Assunção José Afonso , Gupta Rajeev , Nacheva Elisabeth P. , Henderson Stephen , Herrero Javier , Linch David C. , de Bruin Robertus A.M. , Mansour Marc R.
Published: March 2024

Abstract
Loss-of-function mutations of EZH2, the enzymatic component of PRC2, have been associated with poor outcome and chemotherapy resistance in T-cell acute lymphoblastic leukemia (T-ALL). Using isogenic T-ALL cells, with and without CRISPR/Cas9–induced EZH2-inactivating mutations, we performed a cell-based synthetic lethal drug screen. EZH2-deficient cells exhibited increased sensitivity to structurally diverse inhibitors of CHK1, an interaction that could be validated genetically. Furthermore, small-molecule inhibition of CHK1 had efficacy in delaying tumor progression in isogenic EZH2-deficient, but not EZH2 wild-type, T-ALL cells in vivo, as well as in a primary cell model of PRC2-mutant ALL. Mechanistically, EZH2 deficiency resulted in a gene-expression signature of immature T-ALL cells, marked transcriptional upregulation of MYCN, increased replication stress, and enhanced dependency on CHK1 for cell survival. Finally, we demonstrate this phenotype is mediated through derepression of a distal PRC2-regulated MYCN enhancer. In conclusion, we highlight a novel and clinically exploitable pathway in high-risk EZH2-mutated T-ALL.
Significance:
Loss-of-function mutations of PRC2 genes are associated with chemotherapy resistance in T-ALL, yet no specific therapy for this aggressive subtype is currently clinically available. Our work demonstrates that loss of EZH2 activity leads to MYCN-driven replication stress, resulting in increased sensitivity to CHK1 inhibition, a finding with immediate clinical relevance.

This article is highlighted in the In This Issue feature, p. 890
Data from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia
Authors: Zhou Yalu , Han Cuijuan , Wang Eric , Lorch Adam H. , Serafin Valentina , Cho Byoung-Kyu , Gutierrez Diaz Blanca T. , Calvo Julien , Fang Celestia , Khodadadi-Jamayran Alireza , Tabaglio Tommaso , Marier Christian , Kuchmiy Anna , Sun Limin , Yacu George , Filip Szymon K. , Jin Qi , Takahashi Yoh-Hei , Amici David R. , Rendleman Emily J. , Rawat Radhika , Bresolin Silvia , Paganin Maddalena , Zhang Cheng , Li Hu , Kandela Irawati , Politanska Yuliya , Abdala-Valencia Hiam , Mendillo Marc L. , Zhu Ping , Palhais Bruno , Van Vlierberghe Pieter , Taghon Tom , Aifantis Iannis , Goo Young Ah , Guccione Ernesto , Heguy Adriana , Tsirigos Aristotelis , Wee Keng Boon , Mishra Rama K. , Pflumio Francoise , Accordi Benedetta , Basso Giuseppe , Ntziachristos Panagiotis
Published: March 2024

Abstract
Splicing alterations are common in diseases such as cancer, where mutations in splicing factor genes are frequently responsible for aberrant splicing. Here we present an alternative mechanism for splicing regulation in T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the splicing machinery via deubiquitination. We demonstrate there are extensive exon skipping changes in disease, affecting proteasomal subunits, cell-cycle regulators, and the RNA machinery. We present that the serine/arginine-rich splicing factors (SRSF), controlling exon skipping, are critical for leukemia cell survival. The ubiquitin-specific peptidase 7 (USP7) regulates SRSF6 protein levels via active deubiquitination, and USP7 inhibition alters the exon skipping pattern and blocks T-ALL growth. The splicing inhibitor H3B-8800 affects splicing of proteasomal transcripts and proteasome activity and acts synergistically with proteasome inhibitors in inhibiting T-ALL growth. Our study provides the proof-of-principle for regulation of splicing factors via deubiquitination and suggests new therapeutic modalities in T-ALL.
Significance:
Our study provides a new proof-of-principle for posttranslational regulation of splicing factors independently of mutations in aggressive T-cell leukemia. It further suggests a new drug combination of splicing and proteasomal inhibitors, a concept that might apply to other diseases with or without mutations affecting the splicing machinery.

This article is highlighted in the In This Issue feature, p. 1241
Data from Gain-of-Function RHOA Mutations Promote Focal Adhesion Kinase Activation and Dependency in Diffuse Gastric Cancer
Authors: Zhang Haisheng , Schaefer Antje , Wang Yichen , Hodge Richard G. , Blake Devon R. , Diehl J. Nathaniel , Papageorge Alex G. , Stachler Matthew D. , Liao Jennifer , Zhou Jin , Wu Zhong , Akarca Fahire G. , de Klerk Leonie K. , Derks Sarah , Pierobon Mariaelena , Hoadley Katherine A. , Wang Timothy C. , Church George , Wong Kwok-Kin , Petricoin Emanuel F. , Cox Adrienne D. , Lowy Douglas R. , Der Channing J. , Bass Adam J.
Published: March 2024

Abstract
Diffuse gastric cancer (DGC) is a lethal malignancy lacking effective systemic therapy. Among the most provocative recent results in DGC has been that of highly recurrent missense mutations in the GTPase RHOA. The function of these mutations has remained unresolved. We demonstrate that RHOAY42C, the most common RHOA mutation in DGC, is a gain-of-function oncogenic mutant, and that expression of RHOAY42C with inactivation of the canonical tumor suppressor Cdh1 induces metastatic DGC in a mouse model. Biochemically, RHOAY42C exhibits impaired GTP hydrolysis and enhances interaction with its effector ROCK. RHOAY42C mutation and Cdh1 loss induce actin/cytoskeletal rearrangements and activity of focal adhesion kinase (FAK), which activates YAP–TAZ, PI3K–AKT, and β-catenin. RHOAY42C murine models were sensitive to FAK inhibition and to combined YAP and PI3K pathway blockade. These results, coupled with sensitivity to FAK inhibition in patient-derived DGC cell lines, nominate FAK as a novel target for these cancers.
Significance:
The functional significance of recurrent RHOA mutations in DGC has remained unresolved. Through biochemical studies and mouse modeling of the hotspot RHOAY42C mutation, we establish that these mutations are activating, detail their effects upon cell signaling, and define how RHOA-mediated FAK activation imparts sensitivity to pharmacologic FAK inhibitors.

See related commentary by Benton and Chernoff, p. 182.

This article is highlighted in the In This Issue feature, p. 161
Data from Somatic HLA Class I Loss Is a Widespread Mechanism of Immune Evasion Which Refines the Use of Tumor Mutational Burden as a Biomarker of Checkpoint Inhibitor Response
Authors: Montesion Meagan , Murugesan Karthikeyan , Jin Dexter X. , Sharaf Radwa , Sanchez Nora , Guria Ameet , Minker Max , Li Gerald , Fisher Virginia , Sokol Ethan S. , Pavlick Dean C. , Moore Jay A. , Braly Alan , Singal Gaurav , Fabrizio David , Comment Leah A. , Rizvi Naiyer A. , Alexander Brian M. , Frampton Garrett M. , Hegde Priti S. , Albacker Lee A.
Published: March 2024

Abstract
Neoantigen presentation arises as a result of tumor-specific mutations and is a critical component of immune surveillance that can be abrogated by somatic LOH of the human leukocyte antigen class I (HLA-I) locus. To understand the role of HLA-I LOH in oncogenesis and treatment, we utilized a pan-cancer genomic dataset of 83,644 patient samples, a small subset of which had treatment outcomes with immune checkpoint inhibitors (ICI). HLA-I LOH was common (17%) and unexpectedly had a nonlinear relationship with tumor mutational burden (TMB). HLA-I LOH was frequent at intermediate TMB, yet prevalence decreased above 30 mutations/megabase, suggesting highly mutated tumors require alternate immune evasion mechanisms. In ICI-treated patients with nonsquamous non–small cell lung cancer, HLA-I LOH was a significant negative predictor of overall survival. Survival prediction improved when combined with TMB, suggesting TMB with HLA-I LOH may better identify patients likely to benefit from ICIs.
Significance:
This work shows the pan-cancer landscape of HLA-I LOH, revealing an unexpected “Goldilocks” relationship between HLA-I LOH and TMB, and demonstrates HLA-I LOH as a significant negative predictor of outcomes after ICI treatment. These data informed a combined predictor of outcomes after ICI and have implications for tumor vaccine development.

This article is highlighted in the In This Issue feature, p. 211
Data from First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma
Authors: Kim Richard D. , Sarker Debashis , Meyer Tim , Yau Thomas , Macarulla Teresa , Park Joong-Won , Choo Su Pin , Hollebecque Antoine , Sung Max W. , Lim Ho-Yeong , Mazzaferro Vincenzo , Trojan Joerg , Zhu Andrew X. , Yoon Jung-Hwan , Sharma Sunil , Lin Zhong-Zhe , Chan Stephen L. , Faivre Sandrine , Feun Lynn G. , Yen Chia-Jui , Dufour Jean-Francois , Palmer Daniel H. , Llovet Josep M. , Manoogian Melissa , Tugnait Meera , Stransky Nicolas , Hagel Margit , Kohl Nancy E. , Lengauer Christoph , Sherwin Cori Ann , Schmidt-Kittler Oleg , Hoeflich Klaus P. , Shi Hongliang , Wolf Beni B. , Kang Yoon-Koo
Published: March 2024

Abstract
Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7–not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC.
Significance:
Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection.

See related commentary by Subbiah and Pal, p. 1646.

This article is highlighted in the In This Issue feature, p. 1631