bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from First-in-Human Trial of a STAT3 Decoy Oligonucleotide in Head and Neck Tumors: Implications for Cancer Therapy
Authors: Sen Malabika , Thomas Sufi M. , Kim Seungwon , Yeh Joanne I. , Ferris Robert L. , Johnson Jonas T. , Duvvuri Umamaheswar , Lee Jessica , Sahu Nivedita , Joyce Sonali , Freilino Maria L. , Shi Haibin , Li Changyou , Ly Danith , Rapireddy Srinivas , Etter Jonathan P. , Li Pui-Kai , Wang Lin , Chiosea Simion , Seethala Raja R. , Gooding William E. , Chen Xiaomin , Kaminski Naftali , Pandit Kusum , Johnson Daniel E. , Grandis Jennifer R.
Published: March 2024

Abstract
Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as “undruggable.” We developed a decoy targeting STAT3 and conducted a phase 0 trial. Expression levels of STAT3 target genes were decreased in head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexaethylene glycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development.

Significance: This is the first study of a STAT3-selective inhibitor in humans and the first evidence that a transcription factor decoy can be modified to enable systemic delivery. These findings have therapeutic implications beyond STAT3 to other “undruggable” targets in human cancers. Cancer Discov; 2(8); 694–705. ©2012 AACR.

Read the Commentary on this article by Koppikar et al., p. 670.

This article is highlighted in the In This Issue feature, p. 653.
Data from miR-23a Promotes the Transition from Indolent to Invasive Colorectal Cancer
Authors: Jahid Sohail , Sun Jian , Edwards Robert A. , Dizon Diana , Panarelli Nicole C. , Milsom Jeffrey W. , Sikandar Shaheen S. , Gümüş Zeynep H. , Lipkin Steven M.
Published: March 2024

Abstract
Colorectal cancer is a classic example of a tumor that progresses through multiple distinct stages in its evolution. To understand the mechanisms regulating the transition from indolent to invasive disease, we profiled somatic copy number alterations in noninvasive adenomas and invasive adenocarcinomas from Apc and DNA mismatch repair (MMR) mutant mouse models. We identified a recurrent amplicon on mouse chromosome 8 that encodes microRNA (miRNA) 23a and -27a (miR). miR-23a and -27a levels are upregulated in mouse intestinal adenocarcinomas, primary tumors from patients with stage I/II colorectal cancers, as well as in human colorectal cancer cell lines and cancer stem cells. Functionally, miR-23a promotes the migration and invasion of colorectal cancer cells and stem cells, whereas miR-27a primarily promotes proliferation. We computationally and experimentally validated that metastasis suppressor 1 (MTSS1) is a direct miR-23a target and similarly validated that the ubiquitin ligase FBXW7 is a direct miR-27a target. Analyses of computationally predicted target genes in microarray data sets of patients with colorectal cancers are consistent with a role for miR-23a, but not miR-27a, specifically in invasive colorectal cancers.

Significance: Understanding the mechanisms regulating the transition from indolent adenomas to invasive and metastatic colorectal cancers is critical to improving patient outcomes. Our study highlights roles of miR-23a and miR-27a in tumor progression and supports a potential mechanistic role for miR-23a in the transition from indolent to invasive colorectal cancers. Cancer Discov; 2(6); 540–53. © 2012 AACR.

This article is highlighted in the In This Issue feature, p. 473
Data from Metabolomics Strategy Reveals Subpopulation of Liposarcomas Sensitive to Gemcitabine Treatment
Authors: Braas Daniel , Ahler Ethan , Tam Brenna , Nathanson David , Riedinger Mirielle , Benz Matthias R. , Smith Kathleen B. , Eilber Fritz C. , Witte Owen N. , Tap William D. , Wu Hong , Christofk Heather R.
Published: March 2024

Abstract
Unlike many cancers that exhibit glycolytic metabolism, high-grade liposarcomas often exhibit low 2[18F]fluoro-2-deoxy-d-glucose uptake by positron emission tomography (PET), despite rapid tumor growth. Here, we used liquid chromatography tandem mass spectrometry to identify carbon sources taken up by liposarcoma cell lines derived from xenograft tumors in patients. Interestingly, we found that liposarcoma cell lines consume nucleosides from culture media, suggesting nucleoside salvage pathway activity. The nucleoside salvage pathway is dependent on deoxycytidine kinase (dCK) and can be imaged in vivo by PET with 1-(2′-deoxy-2′-[18F]fluoroarabinofuranosyl) cytosine (FAC). We found that liposarcoma cell lines and xenograft tumors exhibit dCK activity and dCK-dependent FAC uptake in vitro and in vivo. In addition, liposarcoma cell lines and xenograft tumors are sensitive to treatment with the nucleoside analogue prodrug gemcitabine, and gemcitabine sensitivity is dependent on dCK expression. Elevated dCK activity is evident in 7 of 68 clinical liposarcoma samples analyzed. These data suggest that a subpopulation of liposarcoma patients have tumors with nucleoside salvage pathway activity that can be identified noninvasively using [18F]-FAC–PET and targeted using gemcitabine.

Significance: Patients with high-grade liposarcoma have poor prognoses and often fail to respond to chemotherapy. This report identifies elevated nucleoside salvage activity in a subset of liposarcomas that are identifiable using noninvasive PET imaging with FAC and that are sensitive to gemcitabine. Thus, we suggest a new treatment paradigm for liposarcoma patients that uses [18F]-FAC-PET in the clinic to delineate gemcitabine responders from nonresponders. Cancer Discov; 2(12); 1109–17. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 1065
Data from PPM1H Is a p27 Phosphatase Implicated in Trastuzumab Resistance
Authors: Lee-Hoeflich Si Tuen , Pham Thinh Q. , Dowbenko Don , Munroe Xander , Lee James , Li Li , Zhou Wei , Haverty Peter M. , Pujara Kanan , Stinson Jeremy , Chan Sara M. , Eastham-Anderson Jeffrey , Pandita Ajay , Seshagiri Somasekar , Hoeflich Klaus P. , Turashvili Gulisa , Gelmon Karen A. , Aparicio Samuel A. , Davis David P. , Sliwkowski Mark X. , Stern Howard M.
Published: March 2024

Abstract
The HER2 oncogene is overexpressed or amplified in 20% of breast cancers. HER2-positive cancer historically portends a poor prognosis, but the HER2-targeted therapy trastuzumab mitigates this otherwise ominous distinction. Nevertheless, some patients suffer disease recurrence despite trastuzumab, and metastatic disease remains largely incurable due to innate and acquired resistance. Thus, understanding trastuzumab resistance remains an unmet medical need. Through RNA interference screening, we discovered that knockdown of the serine/threonine phosphatase PPM1H confers trastuzumab resistance via reduction in protein levels of the tumor suppressor p27. PPM1H dephosphorylates p27 at threonine 187, thus removing a signal for proteasomal degradation. We further determined that patients whose tumors express low levels of PPM1H trend towards worse clinical outcome on trastuzumab. Identifying PPM1H as a novel p27 phosphatase reveals new insight into how cancer cells destabilize a well-recognized tumor suppressor. Furthermore, low PPM1H expression may identify a subset of HER2-positive tumors that are harder to treat.

Significance: PPM1H is identified as a phosphatase impacting p27 stability. Low expression of PPM1H may be associated with poor outcome in breast cancer. Cancer Discovery; 1(4); 326–337. ©2011 AACR.

Read the Commentary on this article by Aceto and Bentires-Alj, p. 285

This article is highlighted in the In This Issue feature, p. 275
Data from Targeting C4-Demethylating Genes in the Cholesterol Pathway Sensitizes Cancer Cells to EGF Receptor Inhibitors via Increased EGF Receptor Degradation
Authors: Sukhanova Anna , Gorin Andrey , Serebriiskii Ilya G. , Gabitova Linara , Zheng Hui , Restifo Diana , Egleston Brian L. , Cunningham David , Bagnyukova Tetyana , Liu Hanqing , Nikonova Anna , Adams Gregory P. , Zhou Yan , Yang Dong-Hua , Mehra Ranee , Burtness Barbara , Cai Kathy Q. , Klein-Szanto Andres , Kratz Lisa E. , Kelley Richard I. , Weiner Louis M. , Herman Gail E. , Golemis Erica A. , Astsaturov Igor
Published: March 2024

Abstract
Persistent signaling by the oncogenic EGF receptor (EGFR) is a major source of cancer resistance to EGFR targeting. We established that inactivation of 2 sterol biosynthesis pathway genes, SC4MOL (sterol C4-methyl oxidase–like) and its partner, NSDHL (NADP-dependent steroid dehydrogenase–like), sensitized tumor cells to EGFR inhibitors. Bioinformatics modeling of interactions for the sterol pathway genes in eukaryotes allowed us to hypothesize and then extensively validate an unexpected role for SC4MOL and NSDHL in controlling the signaling, vesicular trafficking, and degradation of EGFR and its dimerization partners, ERBB2 and ERBB3. Metabolic block upstream of SC4MOL with ketoconazole or CYP51A1 siRNA rescued cancer cell viability and EGFR degradation. Inactivation of SC4MOL markedly sensitized A431 xenografts to cetuximab, a therapeutic anti-EGFR antibody. Analysis of Nsdhl-deficient Bpa1H/+ mice confirmed dramatic and selective loss of internalized platelet-derived growth factor receptor in fibroblasts, and reduced activation of EGFR and its effectors in regions of skin lacking NSDHL.

Significance: This work identifies a critical role for SC4MOL and NSDHL in the regulation of EGFR signaling and endocytic trafficking and suggests novel strategies to increase the potency of EGFR antagonists in tumors. Cancer Discov; 3(1); 96–111. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 1
Data from Kinetics of Inhibitor Cycling Underlie Therapeutic Disparities between EGFR-Driven Lung and Brain Cancers
Authors: Barkovich Krister J. , Hariono Sujatmi , Garske Adam L. , Zhang Jie , Blair Jimmy A. , Fan Qi-Wen , Shokat Kevan M. , Nicolaides Theodore , Weiss William A.
Published: March 2024

Abstract
Although mutational activation of the epidermal growth factor receptor (EGFR) features prominently in glioma and non–small cell lung cancer (NSCLC), inhibitors of EGFR improve survival only in patients with NCSLC. To understand how mutations in EGFR influence response to therapy, we generated glioma cells expressing either glioma- or NSCLC-derived alleles and quantified kinase-site occupancy by clinical inhibitors with the use of a novel affinity probe and kinetic methodology. At equivalent doses, erlotinib achieved lower kinase-site occupancy in glioma-derived EGFRvIII compared with NSCLC-derived EGFR mutants. Kinase-site occupancy correlated directly with cell-cycle arrest. EGFRvIII released erlotinib rapidly compared with wild-type EGFR, whereas NSCLC-derived mutants released erlotinib slowly.

Significance: These data suggest that kinase-site occupancy is a biomarker for efficacy of EGFR inhibitors, that rapid binding and release of erlotinib in glioma-derived EGFRvIII opposes the blockade of downstream signaling, and that slower cycling of erlotinib within the active site of NSCLC-derived mutants underlies their improved clinical response. Cancer Discov; 2(5); 450–7. ©2012 AACR.

Read the Commentary on this article by Park and Lemmon, p. 398.

This article is highlighted in the In This Issue feature, p. 377.
Data from PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer
Authors: Costa Carlotta , Wang Ye , Ly Amy , Hosono Yasuyuki , Murchie Ellen , Walmsley Charlotte S. , Huynh Tiffany , Healy Christopher , Peterson Rachel , Yanase Shogo , Jakubik Charles T. , Henderson Laura E. , Damon Leah J. , Timonina Daria , Sanidas Ioannis , Pinto Christopher J. , Mino-Kenudson Mari , Stone James R. , Dyson Nicholas J. , Ellisen Leif W. , Bardia Aditya , Ebi Hiromichi , Benes Cyril H. , Engelman Jeffrey A. , Juric Dejan
Published: March 2024

Abstract
The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies.
Significance:
Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.

This article is highlighted in the In This Issue feature, p. 1
Data from High Frequency of PIK3R1 and PIK3R2 Mutations in Endometrial Cancer Elucidates a Novel Mechanism for Regulation of PTEN Protein Stability
Authors: Cheung Lydia W.T. , Hennessy Bryan T. , Li Jie , Yu Shuangxing , Myers Andrea P. , Djordjevic Bojana , Lu Yiling , Stemke-Hale Katherine , Dyer Mary D. , Zhang Fan , Ju Zhenlin , Cantley Lewis C. , Scherer Steven E. , Liang Han , Lu Karen H. , Broaddus Russell R. , Mills Gordon B.
Published: March 2024

Abstract
We demonstrate that phosphatidylinositol 3-kinase (PI3K) pathway aberrations occur in >80% of endometrioid endometrial cancers, with coordinate mutations of multiple PI3K pathway members being more common than predicted by chance. PIK3R1 (p85α) mutations occur at a higher rate in endometrial cancer than in any other tumor lineage, and PIK3R2 (p85β), not previously demonstrated to be a cancer gene, is also frequently mutated. The dominant activation event in the PI3K pathway appears to be PTEN protein loss. However, in tumors with retained PTEN protein, PI3K pathway mutations phenocopy PTEN loss, resulting in pathway activation. KRAS mutations are common in endometrioid tumors activating independent events from PI3K pathway aberrations. Multiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85α dimers bind and stabilize PTEN. Taken together, the PI3K pathway represents a critical driver of endometrial cancer pathogenesis and a novel therapeutic target.

Significance: Our data indicate that the PI3K pathway is targeted in the vast majority of endometrioid endometrial cancers leading to PI3K pathway activation. Frequent oncogenic mutations in PIK3R1 and PIK3R2 provide evidence for their role in endometrial cancer pathophysiology with patient-specific mutations revealing a novel mechanism by which p85α regulates the PI3K pathway through stabilizing PTEN. Cancer Discovery; 1(2); 170–85. ©2011 AACR.

Read the Commentary on this article by Herrero-Gonzalez and Di Cristofano, p. 106

This article is highlighted in the In This Issue feature, p. 91
Data from microRNA Regulatory Network Inference Identifies miR-34a as a Novel Regulator of TGF-β Signaling in Glioblastoma
Authors: Genovese Giannicola , Ergun Ayla , Shukla Sachet A. , Campos Benito , Hanna Jason , Ghosh Papia , Quayle Steven N. , Rai Kunal , Colla Simona , Ying Haoqiang , Wu Chang-Jiun , Sarkar Sharmistha , Xiao Yonghong , Zhang Jianhua , Zhang Hailei , Kwong Lawrence , Dunn Katherine , Wiedemeyer Wolf Ruprecht , Brennan Cameron , Zheng Hongwu , Rimm David L. , Collins James J. , Chin Lynda
Published: March 2024

Abstract
Leveraging The Cancer Genome Atlas (TCGA) multidimensional data in glioblastoma, we inferred the putative regulatory network between microRNA and mRNA using the Context Likelihood of Relatedness modeling algorithm. Interrogation of the network in context of defined molecular subtypes identified 8 microRNAs with a strong discriminatory potential between proneural and mesenchymal subtypes. Integrative in silico analyses, a functional genetic screen, and experimental validation identified miR-34a as a tumor suppressor in proneural subtype glioblastoma. Mechanistically, in addition to its direct regulation of platelet-derived growth factor receptor-alpha (PDGFRA), promoter enrichment analysis of context likelihood of relatedness–inferred mRNA nodes established miR-34a as a novel regulator of a SMAD4 transcriptional network. Clinically, miR-34a expression level is shown to be prognostic, where miR-34a low-expressing glioblastomas exhibited better overall survival. This work illustrates the potential of comprehensive multidimensional cancer genomic data combined with computational and experimental models in enabling mechanistic exploration of relationships among different genetic elements across the genome space in cancer.

Significance: We illustrate here that network modeling of complex multidimensional cancer genomic data can generate a framework in which to explore the biology of cancers, leading to discovery of new pathogenetic insights as well as potential prognostic biomarkers. Specifically in glioblastoma, within the context of the global network, promoter enrichment analysis of network edges uncovered a novel regulation of TGF-β signaling via a Smad4 transcriptomic network by miR-34a. Cancer Discov; 2(8); 736–49. ©2012 AACR.

Read the Commentary on this article by Babic et al., p. 676.

This article is highlighted in the In This Issue feature, p. 653.
Data from PTEN Is a Major Tumor Suppressor in Pancreatic Ductal Adenocarcinoma and Regulates an NF-κB–Cytokine Network
Authors: Ying Haoqiang , Elpek Kutlu G. , Vinjamoori Anant , Zimmerman Stephanie M. , Chu Gerald C. , Yan Haiyan , Fletcher-Sananikone Eliot , Zhang Hailei , Liu Yingchun , Wang Wei , Ren Xiaojia , Zheng Hongwu , Kimmelman Alec C. , Paik Ji-hye , Lim Carol , Perry Samuel R. , Jiang Shan , Malinn Brian , Protopopov Alexei , Colla Simona , Xiao Yonghong , Hezel Aram F. , Bardeesy Nabeel , Turley Shannon J. , Wang Y. Alan , Chin Lynda , Thayer Sarah P. , DePinho Ronald A.
Published: March 2024

Abstract
Initiation of pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic KRAS mutation, and disease progression is associated with frequent loss of tumor suppressors. In this study, human PDAC genome analyses revealed frequent deletion of the PTEN gene as well as loss of expression in primary tumor specimens. A potential role for PTEN as a haploinsufficient tumor suppressor is further supported by mouse genetic studies. The mouse PDAC driven by oncogenic Kras mutation and Pten deficiency also sustains spontaneous extinction of Ink4a expression and shows prometastatic capacity. Unbiased transcriptomic analyses established that combined oncogenic Kras and Pten loss promotes marked NF-κB activation and its cytokine network, with accompanying robust stromal activation and immune cell infiltration with known tumor-promoting properties. Thus, PTEN/phosphoinositide 3-kinase (PI3K) pathway alteration is a common event in PDAC development and functions in part to strongly activate the NF-κB network, which may serve to shape the PDAC tumor microenvironment.

Significance: Detailed molecular genetics studies established that PTEN operates as a haploinsufficient tumor suppressor to promote metastatic PDAC development. The strong activation of the NF-κB–cytokine program in Pten-deficient tumors provides additional avenues for targeted therapies in tumors with altered PI3K regulation. Cancer Discovery; 1(2); 158–69. ©2011 AACR.

Read the Commentary on this article by Chiao and Ling, p. 103

This article is highlighted in the In This Issue feature, p. 91
Data from Genetic and Functional Studies Implicate HIF1α as a 14q Kidney Cancer Suppressor Gene
Authors: Shen Chuan , Beroukhim Rameen , Schumacher Steven E. , Zhou Jing , Chang Michelle , Signoretti Sabina , Kaelin William G.
Published: March 2024

Abstract
Kidney cancers often delete chromosome 3p, spanning the VHL tumor suppressor gene, and chromosome 14q, which presumably harbors ≥1 tumor suppressor genes. pVHL inhibits the hypoxia-inducible transcription factor (HIF), and HIF2α is a kidney cancer oncoprotein. In this article, we identify focal, homozygous deletions of the HIF1α locus on 14q in clear cell renal carcinoma cell lines. Wild-type HIF1α suppresses renal carcinoma growth, but the products of these altered loci do not. Conversely, downregulation of HIF1α in HIF1α-proficient lines promotes tumor growth. HIF1α activity is diminished in 14q-deleted kidney cancers, and all somatic HIF1α mutations identified in kidney cancers tested to date are loss of function. Therefore, HIF1α has the credentials of a kidney cancer suppressor gene.

Significance: Deletion of 14q is a frequent event in clear cell renal carcinoma and portends a poor prognosis. In this study, we provide genetic and functional evidence that HIF1α is a target of 14q loss in kidney cancer. Cancer Discovery; 1(3); 222–35. © 2011 AACR.

Read the Commentary on this article by Pal and Figlin, p. 198

This article is highlighted in the In This Issue feature, p. 189
Data from A Chimeric RNA Characteristic of Rhabdomyosarcoma in Normal Myogenesis Process
Authors: Yuan Huiling , Qin Fujun , Movassagh Mercedeh , Park Hong , Golden Wendy , Xie Zhongqiu , Zhang Peng , Sklar Jeffrey , Li Hui
Published: March 2024

Abstract
Gene fusions and their chimeric products are common features of neoplasia. Given that many cancers arise by the dysregulated recapitulation of processes in normal development, we hypothesized that comparable chimeric gene products may exist in normal cells. Here, we show that a chimeric RNA, PAX3–FOXO1, identical to that found in alveolar rhabdomyosarcoma, is transiently present in cells undergoing differentiation from pluripotent cells into skeletal muscle. Unlike cells of rhabdomyosarcoma, these cells do not seem to harbor the t(2;13) chromosomal translocation. Importantly, both PAX3–FOXO1 RNA and protein could be detected in the samples of normal fetal muscle. Overexpression of the chimera led to continuous expression of MYOD and MYOG—two myogenic markers that are overexpressed in rhabdomyosarcoma cells. Our results are consistent with a developmental role of a specific chimeric RNA generated in normal cells without the corresponding chromosomal rearrangement at the DNA level seen in neoplastic cells presumably of the same lineage.

Significance: A chimeric fusion RNA, PAX3–FOXO1, associated with alveolar rhabdomyosarcoma, is also present in normal non-cancer cells and tissues. Its transient expression nature and the absence of t(2;13) chromosomal translocation are consistent with a posttranscriptional mechanism. When constantly expressed, PAX3–FOXO1 interfered with the muscle differentiation process, which presumably contributes to tumorigenesis. Cancer Discov; 3(12); 1394–1403. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 1317
Data from Autophagy Is Critical for Pancreatic Tumor Growth and Progression in Tumors with p53 Alterations
Authors: Yang Annan , Rajeshkumar N.V. , Wang Xiaoxu , Yabuuchi Shinichi , Alexander Brian M. , Chu Gerald C. , Von Hoff Daniel D. , Maitra Anirban , Kimmelman Alec C.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp53, we demonstrate that although genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. In addition, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Finally, a mouse preclinical trial using cohorts of genetically characterized patient-derived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together, our data support the critical role of autophagy in pancreatic cancer and show that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status.

Significance: Recently, a mouse model with embryonic homozygous Trp53 deletion showed paradoxical effects of autophagy inhibition. We used a mouse model with Trp53 LOH (similar to human tumors), tumor cell lines, and patient-derived xenografts to show that p53 status does not affect response to autophagy inhibition. These findings have important implications on ongoing clinical trials. Cancer Discov; 4(8); 905–13. ©2014 AACR.

See related commentary by Amaravadi and Debnath, p. 873

This article is highlighted in the In This Issue feature, p. 855
Data from Haploinsufficiency of an RB–E2F1–Condensin II Complex Leads to Aberrant Replication and Aneuploidy
Authors: Coschi Courtney H. , Ishak Charles A. , Gallo David , Marshall Aren , Talluri Srikanth , Wang Jianxin , Cecchini Matthew J. , Martens Alison L. , Percy Vanessa , Welch Ian , Boutros Paul C. , Brown Grant W. , Dick Frederick A.
Published: March 2024

Abstract
Genome instability is a characteristic of malignant cells; however, evidence for its contribution to tumorigenesis has been enigmatic. In this study, we demonstrate that the retinoblastoma protein, E2F1, and Condensin II localize to discrete genomic locations including major satellite repeats at pericentromeres. In the absence of this complex, aberrant replication ensues followed by defective chromosome segregation in mitosis. Surprisingly, loss of even one copy of the retinoblastoma gene reduced recruitment of Condensin II to pericentromeres and caused this phenotype. Using cancer genome data and gene-targeted mice, we demonstrate that mutation of one copy of RB1 is associated with chromosome copy-number variation in cancer. Our study connects DNA replication and chromosome structure defects with aneuploidy through a dosage-sensitive complex at pericentromeric repeats.

Significance: Genome instability is inherent to most cancers and is the basis for selective killing of cancer cells by genotoxic therapeutics. In this report, we demonstrate that instability can be caused by loss of a single allele of the retinoblastoma gene that prevents proper replication and condensation of pericentromeric chromosomal regions, leading to elevated levels of aneuploidy in cancer. Cancer Discov; 4(7); 840–53. ©2014 AACR.

See related commentary by Hinds, p. 764

This article is highlighted in the In This Issue feature, p. 745
Data from EPHA2 Is a Mediator of Vemurafenib Resistance and a Novel Therapeutic Target in Melanoma
Authors: Miao Benchun , Ji Zhenyu , Tan Li , Taylor Michael , Zhang Jianming , Choi Hwan Geun , Frederick Dennie T. , Kumar Raj , Wargo Jennifer A. , Flaherty Keith T. , Gray Nathanael S. , Tsao Hensin
Published: March 2024

Abstract
BRAFV600E is the most common oncogenic lesion in melanoma and results in constitutive activation of the MAPK pathway and uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize oncogenic signaling, restrain cellular growth, and improve patient outcome. Although several mechanisms of vemurafenib resistance have been described, directed solutions to overcome these resistance lesions are still lacking. Herein, we found that vemurafenib resistance can be (i) mediated by EPHA2, a member of the largest receptor tyrosine kinases (RTK) subfamily erythropoietin-producing hepatocellular (EPH) receptors, and (ii) associated with a greater phenotypic dependence on EPHA2. Furthermore, we developed a series of first-in-class EPHA2 inhibitors and show that these new compounds potently induce apoptosis, suppress viability, and abrogate tumorigenic growth of melanoma cells, including those that are resistant to vemurafenib. These results provide proof of concept that RTK-guided growth, and therapeutic resistance, can be prospectively defined and selectively targeted.

Significance: In this study, we show that resistance to selective BRAF inhibitors can be mediated by the RTK EPHA2. Furthermore, direct targeting of EPHA2 can successfully suppress melanoma growth and mitigate therapeutic resistance. Cancer Discov; 5(3); 274–87. ©2014 AACR.

See related article by Paraiso et al., p. 264

This article is highlighted in the In This Issue feature, p. 213
Data from Cell-Autonomous and Non–Cell-Autonomous Mechanisms of Transformation by Amplified FGFR1 in Lung Cancer
Authors: Malchers Florian , Dietlein Felix , Schöttle Jakob , Lu Xin , Nogova Lucia , Albus Kerstin , Fernandez-Cuesta Lynnette , Heuckmann Johannes M. , Gautschi Oliver , Diebold Joachim , Plenker Dennis , Gardizi Masyar , Scheffler Matthias , Bos Marc , Seidel Danila , Leenders Frauke , Richters André , Peifer Martin , Florin Alexandra , Mainkar Prathama S. , Karre Nagaraju , Chandrasekhar Srivari , George Julie , Silling Steffi , Rauh Daniel , Zander Thomas , Ullrich Roland T. , Reinhardt H. Christian , Ringeisen Francois , Büttner Reinhard , Heukamp Lukas C. , Wolf Jürgen , Thomas Roman K.
Published: March 2024

Abstract
The 8p12 locus (containing the FGFR1 tyrosine kinase gene) is frequently amplified in squamous cell lung cancer. However, it is currently unknown which of the 8p12-amplified tumors are also sensitive to fibroblast growth factor receptor (FGFR) inhibition. We found that, in contrast with other recurrent amplifications, the 8p12 region included multiple centers of amplification, suggesting marked genomic heterogeneity. FGFR1-amplified tumor cells were dependent on FGFR ligands in vitro and in vivo. Furthermore, ectopic expression of FGFR1 was oncogenic, which was enhanced by expression of MYC. We found that MYC was coexpressed in 40% of FGFR1-amplified tumors. Tumor cells coexpressing MYC were more sensitive to FGFR inhibition, suggesting that patients with FGFR1-amplified and MYC-overexpressing tumors may benefit from FGFR inhibitor therapy. Thus, both cell-autonomous and non–cell-autonomous mechanisms of transformation modulate FGFR dependency in FGFR1-amplified lung cancer, which may have implications for patient selection for treatment with FGFR inhibitors.

Significance: Amplification of FGFR1 is one of the most frequent candidate targets in lung cancer. Here, we show that multiple factors affect the tumorigenic potential of FGFR1, thus providing clinical hypotheses for refinement of patient selection. Cancer Discov; 4(2); 246–57. ©2013 AACR.

See related commentary by Lockwood and Politi, p. 152

This article is highlighted in the In This Issue feature, p. 131
Data from HER2 Activating Mutations Are Targets for Colorectal Cancer Treatment
Authors: Kavuri Shyam M. , Jain Naveen , Galimi Francesco , Cottino Francesca , Leto Simonetta M. , Migliardi Giorgia , Searleman Adam C. , Shen Wei , Monsey John , Trusolino Livio , Jacobs Samuel A. , Bertotti Andrea , Bose Ron
Published: March 2024

Abstract
The Cancer Genome Atlas project identified HER2 somatic mutations and gene amplification in 7% of patients with colorectal cancer. Introduction of the HER2 mutations S310F, L755S, V777L, V842I, and L866M into colon epithelial cells increased signaling pathways and anchorage-independent cell growth, indicating that they are activating mutations. Introduction of these HER2 activating mutations into colorectal cancer cell lines produced resistance to cetuximab and panitumumab by sustaining MAPK phosphorylation. HER2 mutants are potently inhibited by low nanomolar doses of the irreversible tyrosine kinase inhibitors neratinib and afatinib. HER2 gene sequencing of 48 cetuximab-resistant, quadruple (KRAS, NRAS, BRAF, and PIK3CA) wild-type (WT) colorectal cancer patient-derived xenografts (PDX) identified 4 PDXs with HER2 mutations. HER2-targeted therapies were tested on two PDXs. Treatment with a single HER2-targeted drug (trastuzumab, neratinib, or lapatinib) delayed tumor growth, but dual HER2-targeted therapy with trastuzumab plus tyrosine kinase inhibitors produced regression of these HER2-mutated PDXs.

Significance: HER2 activating mutations cause EGFR antibody resistance in colorectal cell lines, and PDXs with HER2 mutations show durable tumor regression when treated with dual HER2-targeted therapy. These data provide a strong preclinical rationale for clinical trials targeting HER2 activating mutations in metastatic colorectal cancer. Cancer Discov; 5(8); 832–41. ©2015 AACR.

See related commentary by Pectasides and Bass, p. 799.

This article is highlighted in the In This Issue feature, p. 783
Data from Multifunctional T-cell Analyses to Study Response and Progression in Adoptive Cell Transfer Immunotherapy
Authors: Ma Chao , Cheung Ann F. , Chodon Thinle , Koya Richard C. , Wu Zhongqi , Ng Charles , Avramis Earl , Cochran Alistair J. , Witte Owen N. , Baltimore David , Chmielowski Bartosz , Economou James S. , Comin-Anduix Begonya , Ribas Antoni , Heath James R.
Published: March 2024

Abstract
Adoptive cell transfer (ACT) of genetically engineered T cells expressing cancer-specific T-cell receptors (TCR) is a promising cancer treatment. Here, we investigate the in vivo functional activity and dynamics of the transferred cells by analyzing samples from 3 representative patients with melanoma enrolled in a clinical trial of ACT with TCR transgenic T cells targeted against the melanosomal antigen MART-1. The analyses included evaluating 19 secreted proteins from individual cells from phenotypically defined T-cell subpopulations, as well as the enumeration of T cells with TCR antigen specificity for 36 melanoma antigens. These analyses revealed the coordinated functional dynamics of the adoptively transferred, as well as endogenous, T cells, and the importance of highly functional T cells in dominating the antitumor immune response. This study highlights the need to develop approaches to maintaining antitumor T-cell functionality with the aim of increasing the long-term efficacy of TCR-engineered ACT immunotherapy.

Significance: A longitudinal functional study of adoptively transferred TCR–engineered lymphocytes yielded revealing snapshots for understanding the changes of antitumor responses over time in ACT immunotherapy of patients with advanced melanoma. Cancer Discov; 3(4); 418–29. ©2013 AACR.

See related commentary by Speiser, p. 379

This article is highlighted in the In This Issue feature, p. 363
Data from Reduced NF1 Expression Confers Resistance to EGFR Inhibition in Lung Cancer
Authors: de Bruin Elza C. , Cowell Catherine , Warne Patricia H. , Jiang Ming , Saunders Rebecca E. , Melnick Mary Ann , Gettinger Scott , Walther Zenta , Wurtz Anna , Heynen Guus J. , Heideman Daniëlle A.M. , Gómez-Román Javier , García-Castaño Almudena , Gong Yixuan , Ladanyi Marc , Varmus Harold , Bernards René , Smit Egbert F. , Politi Katerina , Downward Julian
Published: March 2024

Abstract
Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase-activating protein encoded by the NF1 gene. Erlotinib failed to fully inhibit RAS–ERK signaling when neurofibromin levels were reduced. Treatment of neurofibromin-deficient lung cancers with a MAP–ERK kinase (MEK) inhibitor restored sensitivity to erlotinib. Low levels of NF1 expression were associated with primary and acquired resistance of lung adenocarcinomas to EGFR TKIs in patients. These findings identify a subgroup of patients with EGFR-mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors.

Significance: The emergence of resistance to EGFR TKIs is a major clinical challenge in the treatment of lung adenocarcinomas driven by mutations in EGFR. This study suggests that, in a subset of patients, resistance is caused by reduced neurofibromin expression, and that in these cases there may be clinical benefit to combining EGFR TKIs with MEK inhibitors. Cancer Discov; 4(5); 606–19. ©2014 AACR.

See related commentary by Maertens and Cichowski, p. 519

This article is highlighted in the In This Issue feature, p. 495
Data from Intratumoral Heterogeneity in a Trp53-Null Mouse Model of Human Breast Cancer
Authors: Zhang Mei , Tsimelzon Anna , Chang Chi-Hsuan , Fan Cheng , Wolff Andrew , Perou Charles M. , Hilsenbeck Susan G. , Rosen Jeffrey M.
Published: March 2024

Abstract
Intratumoral heterogeneity correlates with clinical outcome and reflects the cellular complexity and dynamics within a tumor. Such heterogeneity is thought to contribute to radio- and chemoresistance because many treatments may target only certain tumor cell subpopulations. A better understanding of the functional interactions between various subpopulations of cells, therefore, may help in the development of effective cancer treatments. We identified a unique subpopulation of tumor cells expressing mesenchymal-like markers in a Trp53-null mouse model of basal-like breast cancer using fluorescence-activated cell sorting and microarray analysis. Both in vitro and in vivo experiments revealed the existence of cross-talk between these “mesenchymal-like” cells and tumor-initiating cells. Knockdown of genes encoding ligands upregulated in the mesenchymal cells and their corresponding receptors in the tumor-initiating cells resulted in reduced tumorigenicity and increased tumor latency. These studies illustrate the non–cell-autonomous properties and importance of cooperativity between tumor subpopulations.

Significance: Intratumoral heterogeneity has been considered one important factor in assessing a patient's initial response to treatment and selecting drug regimens to effectively increase tumor response rate. Elucidating the functional interactions between various subpopulations of tumor cells will help provide important new insights in understanding treatment response and tumor progression. Cancer Discov; 5(5); 520–33. ©2015 AACR.

See related commentary by Brooks and Wicha, p. 469

This article is highlighted in the In This Issue feature, p. 453
Data from Succinate Dehydrogenase Mutation Underlies Global Epigenomic Divergence in Gastrointestinal Stromal Tumor
Authors: Killian J. Keith , Kim Su Young , Miettinen Markku , Smith Carly , Merino Maria , Tsokos Maria , Quezado Martha , Smith William I. , Jahromi Mona S. , Xekouki Paraskevi , Szarek Eva , Walker Robert L. , Lasota Jerzy , Raffeld Mark , Klotzle Brandy , Wang Zengfeng , Jones Laura , Zhu Yuelin , Wang Yonghong , Waterfall Joshua J. , O'Sullivan Maureen J. , Bibikova Marina , Pacak Karel , Stratakis Constantine , Janeway Katherine A. , Schiffman Joshua D. , Fan Jian-Bing , Helman Lee , Meltzer Paul S.
Published: March 2024

Abstract
Gastrointestinal stromal tumors (GIST) harbor driver mutations of signal transduction kinases such as KIT, or, alternatively, manifest loss-of-function defects in the mitochondrial succinate dehydrogenase (SDH) complex, a component of the Krebs cycle and electron transport chain. We have uncovered a striking divergence between the DNA methylation profiles of SDH-deficient GIST (n = 24) versus KIT tyrosine kinase pathway–mutated GIST (n = 39). Infinium 450K methylation array analysis of formalin-fixed paraffin-embedded tissues disclosed an order of magnitude greater genomic hypermethylation relative to SDH-deficient GIST versus the KIT-mutant group (84.9 K vs. 8.4 K targets). Epigenomic divergence was further found among SDH-mutant paraganglioma/pheochromocytoma (n = 29), a developmentally distinct SDH-deficient tumor system. Comparison of SDH-mutant GIST with isocitrate dehydrogenase-mutant glioma, another Krebs cycle–defective tumor type, revealed comparable measures of global hypo- and hypermethylation. These data expose a vital connection between succinate metabolism and genomic DNA methylation during tumorigenesis, and generally implicate the mitochondrial Krebs cycle in nuclear epigenomic maintenance.

Significance: This study shows that SDH deficiency underlies pervasive DNA hypermethylation in multiple tumor lineages, generally defining the Krebs cycle as mitochondrial custodian of the methylome. We propose that this phenomenon may result from a failure of maintenance CpG demethylation, secondary to inhibition of the TET 5-methylcytosine dioxgenase demethylation pathway, by inhibitory metabolites that accumulate in tumors with Krebs cycle dysfunction. Cancer Discov; 3(6); 648–57. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 591
Data from Discovery of Biomarkers Predictive of GSI Response in Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma
Authors: Stoeck Alexander , Lejnine Serguei , Truong Andrew , Pan Li , Wang Hongfang , Zang Chongzhi , Yuan Jing , Ware Chris , MacLean John , Garrett-Engele Philip W. , Kluk Michael , Laskey Jason , Haines Brian B. , Moskaluk Christopher , Zawel Leigh , Fawell Stephen , Gilliland Gary , Zhang Theresa , Kremer Brandon E. , Knoechel Birgit , Bernstein Bradley E. , Pear Warren S. , Liu X. Shirley , Aster Jon C. , Sathyanarayanan Sriram
Published: March 2024

Abstract
Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in patients with TNBC. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD–low tumors without NOTCH1 mutations were resistant.

Significance:NOTCH1 mutations, immunohistochemical staining for activated NOTCH1, and HES4 expression are biomarkers that can be used to identify solid tumors that are likely to respond to GSI-based therapies. Cancer Discov; 4(10); 1154–67. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 1103
Data from Frequent Mutation of the PI3K Pathway in Head and Neck Cancer Defines Predictive Biomarkers
Authors: Lui Vivian W.Y. , Hedberg Matthew L. , Li Hua , Vangara Bhavana S. , Pendleton Kelsey , Zeng Yan , Lu Yiling , Zhang Qiuhong , Du Yu , Gilbert Breean R. , Freilino Maria , Sauerwein Sam , Peyser Noah D. , Xiao Dong , Diergaarde Brenda , Wang Lin , Chiosea Simion , Seethala Raja , Johnson Jonas T. , Kim Seungwon , Duvvuri Umamaheswar , Ferris Robert L. , Romkes Marjorie , Nukui Tomoko , Kwok-Shing Ng Patrick , Garraway Levi A. , Hammerman Peter S. , Mills Gordon B. , Grandis Jennifer R.
Published: March 2024

Abstract
Genomic findings underscore the heterogeneity of head and neck squamous cell carcinoma (HNSCC). Identification of mutations that predict therapeutic response would be a major advance. We determined the mutationally altered, targetable mitogenic pathways in a large HNSCC cohort. Analysis of whole-exome sequencing data from 151 tumors revealed the phosphoinositide 3-kinase (PI3K) pathway to be the most frequently mutated oncogenic pathway (30.5%). PI3K pathway–mutated HNSCC tumors harbored a significantly higher rate of mutations in known cancer genes. In a subset of human papillomavirus-positive tumors, PIK3CA or PIK3R1 was the only mutated cancer gene. Strikingly, all tumors with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSCC progression. Patient-derived tumorgrafts with canonical and noncanonical PIK3CA mutations were sensitive to an mTOR/PI3K inhibitor (BEZ-235), in contrast to PIK3CA–wild-type tumorgrafts. These results suggest that PI3K pathway mutations may serve as predictive biomarkers for treatment selection.

Significance: Treatment options for HNSCC are limited, in part, because of an incomplete understanding of the targetable mutations that “drive” tumor growth. Here, we define a subgroup of HNSCC harboring activating mutations of genes in the PI3K pathway where targeting the pathway shows antitumor efficacy. These results suggest that PI3K pathway mutation assessment may be used to guide HNSCC therapy. Cancer Discov; 3(7); 761–9. ©2013 AACR.

See related commentary by Iglesias-Bartolome et al., p. 722

This article is highlighted in the In This Issue feature, p. 705
Data from PTEN-Deficient Tumors Depend on AKT2 for Maintenance and Survival
Authors: Chin Y. Rebecca , Yuan Xin , Balk Steven P. , Toker Alex
Published: March 2024

Abstract
Loss of PTEN is a common event in many cancers and leads to hyperactivation of the PI3K–AKT signaling pathway. The mechanisms by which AKT isoforms mediate signaling to phenotypes associated with PTEN inactivation in cancer have not been defined. Here, we show that AKT2 is exclusively required for PTEN-deficient prostate tumor spheroid maintenance, whereas AKT1 is dispensable. shRNA silencing of AKT2 but not AKT1 promotes regression of prostate cancer xenografts. Mechanistically, we show that AKT2 silencing upregulates p21 and the proapoptotic protein BAX and downregulates the insulin-like growth factor receptor-1. We also show that p21 is an effector of AKT2 in mediating prostate tumor maintenance. Moreover, AKT2 is also exclusively required for the maintenance and survival of other PTEN-deficient solid tumors, including breast cancer and glioblastoma. These findings identify a specific function for AKT2 in mediating survival of PTEN-deficient tumors and provide a rationale for developing therapeutics targeting AKT2.

Significance: Depletion of AKT2, but not AKT1, induces potent tumor regression in PTEN-deficient prostate cancer xenografts, concomitant with upregulation of p21, which may serve as a potential biomarker for screening AKT2 activity in clinical samples. The specific role of AKT2 in tumor maintenance provides a rationale for the development of isoform-specific inhibitors for patients with PTEN-deficient cancers. Cancer Discov; 4(8); 942–55. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 855