bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Convergent Therapeutic Strategies to Overcome the Heterogeneity of Acquired Resistance in BRAFV600E Colorectal Cancer
Authors: Hazar-Rethinam Mehlika , Kleyman Marianna , Han G. Celine , Liu David , Ahronian Leanne G. , Shahzade Heather A. , Chen Lifeng , Parikh Aparna R. , Allen Jill N. , Clark Jeffrey W. , Kwak Eunice L. , Faris Jason E. , Murphy Janet E. , Hong Theodore S. , Van Seventer Emily E. , Nadres Brandon , Hong Catriona B. , Gurski Joseph M. , Jessop Nicholas A. , Dias-Santagata Dora , Iafrate A. John , Van Allen Eliezer M. , Corcoran Ryan B.
Published: March 2024

Abstract
Clonal heterogeneity associated with acquired resistance presents a critical therapeutic challenge. Whole-exome sequencing of paired tumor biopsies and targeted sequencing of cell-free DNA (cfDNA) from patients with BRAFV600E colorectal cancer receiving BRAF inhibitor combinations identified 14 distinct alterations in MAPK pathway components driving acquired resistance, with as many as eight alterations in a single patient. We developed a pooled clone system to study clonal outgrowth during acquired resistance, in vitro and in vivo. In vitro, the dynamics of individual resistant clones could be monitored in real time in cfDNA isolated from culture media during therapy. Outgrowth of multiple resistant clones was observed during therapy with BRAF, EGFR, and MEK inhibitor combinations. However, ERK inhibition, particularly in combination with BRAF and EGFR inhibition, markedly abrogated clonal outgrowth in vitro and in vivo. Thus, convergent, up-front therapy may suppress outgrowth of heterogeneous clones harboring clinically observed resistance alterations, which may improve clinical outcome.

Significance: We observed heterogeneous, recurrent alterations in the MAPK pathway as key drivers of acquired resistance in BRAFV600E colorectal cancer, with multiple concurrent resistance alterations detectable in individual patients. Using a novel pooled clone system, we identify convergent up-front therapeutic strategies capable of intercepting multiple resistance mechanisms as potential approaches to suppress emergence of acquired resistance. Cancer Discov; 8(4); 417–27. ©2018 AACR.

See related commentary by Janku, p. 389.

See related article by Corcoran et al., p. 428.

This article is highlighted in the In This Issue feature, p. 371
Data from Genomic and Functional Fidelity of Small Cell Lung Cancer Patient-Derived Xenografts
Authors: Drapkin Benjamin J. , George Julie , Christensen Camilla L. , Mino-Kenudson Mari , Dries Ruben , Sundaresan Tilak , Phat Sarah , Myers David T. , Zhong Jun , Igo Peter , Hazar-Rethinam Mehlika H. , Licausi Joseph A. , Gomez-Caraballo Maria , Kem Marina , Jani Kandarp N. , Azimi Roxana , Abedpour Nima , Menon Roopika , Lakis Sotirios , Heist Rebecca S. , Büttner Reinhard , Haas Stefan , Sequist Lecia V. , Shaw Alice T. , Wong Kwok-Kin , Hata Aaron N. , Toner Mehmet , Maheswaran Shyamala , Haber Daniel A. , Peifer Martin , Dyson Nicholas , Thomas Roman K. , Farago Anna F.
Published: March 2024

Abstract
Small cell lung cancer (SCLC) patient-derived xenografts (PDX) can be generated from biopsies or circulating tumor cells (CTC), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical–translational pipeline for tissue collection and an automated microfluidic platform for CTC enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a 2-year timeframe, at 89% and 38% efficiency, respectively. Whole-exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and platinum (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP-naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.

Significance: Effective translational research utilizing SCLC PDX models requires both efficient generation of models from patients and fidelity of those models in representing patient tumor characteristics. We present approaches for efficient generation of PDXs from both biopsies and CTCs, and demonstrate that these models capture the mutational landscape and functional features of the donor tumors. Cancer Discov; 8(5); 600–15. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 517
Data from Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study
Authors: Daver Naval , Garcia-Manero Guillermo , Basu Sreyashi , Boddu Prajwal C. , Alfayez Mansour , Cortes Jorge E. , Konopleva Marina , Ravandi-Kashani Farhad , Jabbour Elias , Kadia Tapan , Nogueras-Gonzalez Graciela M. , Ning Jing , Pemmaraju Naveen , DiNardo Courtney D. , Andreeff Michael , Pierce Sherry A. , Gordon Tauna , Kornblau Steven M. , Flores Wilmer , Alhamal Zainab , Bueso-Ramos Carlos , Jorgensen Jeffrey L. , Patel Keyur P. , Blando Jorge , Allison James P. , Sharma Padmanee , Kantarjian Hagop
Published: March 2024

Abstract
Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22–90) and the median number of prior therapies received was 2 (range, 1–7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)–naïve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4+ Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection.
Significance:
Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3+ bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials.

This article is highlighted in the In This Issue feature, p. 305
Data from Detection and Surveillance of Bladder Cancer Using Urine Tumor DNA
Authors: Dudley Jonathan C. , Schroers-Martin Joseph , Lazzareschi Daniel V. , Shi William Y. , Chen Simon B. , Esfahani Mohammad S. , Trivedi Dharati , Chabon Jacob J. , Chaudhuri Aadel A. , Stehr Henning , Liu Chih Long , Lim Harumi , Costa Helio A. , Nabet Barzin Y. , Sin Mandy L.Y. , Liao Joseph C. , Alizadeh Ash A. , Diehn Maximilian
Published: March 2024

Abstract
Current regimens for the detection and surveillance of bladder cancer are invasive and have suboptimal sensitivity. Here, we present a novel high-throughput sequencing (HTS) method for detection of urine tumor DNA (utDNA) called utDNA CAPP-Seq (uCAPP-Seq) and apply it to 67 healthy adults and 118 patients with early-stage bladder cancer who had urine collected either prior to treatment or during surveillance. Using this targeted sequencing approach, we detected a median of 6 mutations per patient with bladder cancer and observed surprisingly frequent mutations of the PLEKHS1 promoter (46%), suggesting these mutations represent a useful biomarker for detection of bladder cancer. We detected utDNA pretreatment in 93% of cases using a tumor mutation–informed approach and in 84% when blinded to tumor mutation status, with 96% to 100% specificity. In the surveillance setting, we detected utDNA in 91% of patients who ultimately recurred, with utDNA detection preceding clinical progression in 92% of cases. uCAPP-Seq outperformed a commonly used ancillary test (UroVysion, P = 0.02) and cytology and cystoscopy combined (P ≤ 0.006), detecting 100% of bladder cancer cases detected by cytology and 82% that cytology missed. Our results indicate that uCAPP-Seq is a promising approach for early detection and surveillance of bladder cancer.
Significance:
This study shows that utDNA can be detected using HTS with high sensitivity and specificity in patients with early-stage bladder cancer and during post-treatment surveillance, significantly outperforming standard diagnostic modalities and facilitating noninvasive detection, genotyping, and monitoring.

This article is highlighted in the In This Issue feature, p. 453
Data from Epigenetic Identity in AML Depends on Disruption of Nonpromoter Regulatory Elements and Is Affected by Antagonistic Effects of Mutations in Epigenetic Modifiers
Authors: Glass Jacob L. , Hassane Duane , Wouters Bas J. , Kunimoto Hiroyoshi , Avellino Roberto , Garrett-Bakelman Francine E. , Guryanova Olga A. , Bowman Robert , Redlich Shira , Intlekofer Andrew M. , Meydan Cem , Qin Tingting , Fall Mame , Alonso Alicia , Guzman Monica L. , Valk Peter J.M. , Thompson Craig B. , Levine Ross , Elemento Olivier , Delwel Ruud , Melnick Ari , Figueroa Maria E.
Published: March 2024

Abstract
We performed cytosine methylation sequencing on genetically diverse patients with acute myeloid leukemia (AML) and found leukemic DNA methylation patterning is primarily driven by nonpromoter regulatory elements and CpG shores. Enhancers displayed stronger differential methylation than promoters, consisting predominantly of hypomethylation. AMLs with dominant hypermethylation featured greater epigenetic disruption of promoters, whereas those with dominant hypomethylation displayed greater disruption of distal and intronic regions. Mutations in IDH and DNMT3A had opposing and mutually exclusive effects on the epigenome. Notably, co-occurrence of both mutations resulted in epigenetic antagonism, with most CpGs affected by either mutation alone no longer affected in double-mutant AMLs. Importantly, this epigenetic antagonism precedes malignant transformation and can be observed in preleukemic LSK cells from Idh2R140Q or Dnmt3aR882H single-mutant and Idh2R140Q/Dnmt3aR882H double-mutant mice. Notably, IDH/DNMT3A double-mutant AMLs manifested upregulation of a RAS signaling signature and displayed unique sensitivity to MEK inhibition ex vivo as compared with AMLs with either single mutation.

Significance: AML is biologically heterogeneous with subtypes characterized by specific genetic and epigenetic abnormalities. Comprehensive DNA methylation profiling revealed that differential methylation of nonpromoter regulatory elements is a driver of epigenetic identity, that gene mutations can be context-dependent, and that co-occurrence of mutations in epigenetic modifiers can result in epigenetic antagonism. Cancer Discov; 7(8); 868–83. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 783
Data from Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer
Authors: Annala Matti , Vandekerkhove Gillian , Khalaf Daniel , Taavitsainen Sinja , Beja Kevin , Warner Evan W. , Sunderland Katherine , Kollmannsberger Christian , Eigl Bernhard J. , Finch Daygen , Oja Conrad D. , Vergidis Joanna , Zulfiqar Muhammad , Azad Arun A. , Nykter Matti , Gleave Martin E. , Wyatt Alexander W. , Chi Kim N.
Published: March 2024

Abstract
Primary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers.

Significance: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 444–57. ©2018 AACR.

See related commentary by Jayaram et al., p. 392.

This article is highlighted in the In This Issue feature, p. 371
Data from MAPK Pathway Suppression Unmasks Latent DNA Repair Defects and Confers a Chemical Synthetic Vulnerability in BRAF-, NRAS-, and NF1-Mutant Melanomas
Authors: Maertens Ophélia , Kuzmickas Ryan , Manchester Haley E. , Emerson Chloe E. , Gavin Alessandra G. , Guild Caroline J. , Wong Terence C. , De Raedt Thomas , Bowman-Colin Christian , Hatchi Elodie , Garraway Levi A. , Flaherty Keith T. , Pathania Shailja , Elledge Stephen J. , Cichowski Karen
Published: March 2024

Abstract
Although the majority of BRAF-mutant melanomas respond to BRAF/MEK inhibitors, these agents are not typically curative. Moreover, they are largely ineffective in NRAS- and NF1-mutant tumors. Here we report that genetic and chemical suppression of HDAC3 potently cooperates with MAPK pathway inhibitors in all three RAS pathway–driven tumors. Specifically, we show that entinostat dramatically enhances tumor regression when combined with BRAF/MEK inhibitors, in both models that are sensitive or relatively resistant to these agents. Interestingly, MGMT expression predicts responsiveness and marks tumors with latent defects in DNA repair. BRAF/MEK inhibitors enhance these defects by suppressing homologous recombination genes, inducing a BRCA-like state; however, addition of entinostat triggers the concomitant suppression of nonhomologous end-joining genes, resulting in a chemical synthetic lethality caused by excessive DNA damage. Together, these studies identify melanomas with latent DNA repair defects, describe a promising drug combination that capitalizes on these defects, and reveal a tractable therapeutic biomarker.
Significance:
BRAF/MEK inhibitors are not typically curative in BRAF-mutant melanomas and are ineffective in NRAS- and NF1-mutant tumors. We show that HDAC inhibitors dramatically enhance the efficacy of BRAF/MEK inhibitors in sensitive and insensitive RAS pathway–driven melanomas by coordinately suppressing two DNA repair pathways, and identify a clinical biomarker that predicts responsiveness.

See related commentary by Lombard et al., p. 469.

This article is highlighted in the In This Issue feature, p. 453
Data from KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition
Authors: Binkley Michael S. , Jeon Young-Jun , Nesselbush Monica , Moding Everett J. , Nabet Barzin Y. , Almanza Diego , Kunder Christian , Stehr Henning , Yoo Christopher H. , Rhee Siyeon , Xiang Michael , Chabon Jacob J. , Hamilton Emily , Kurtz David M. , Gojenola Linda , Owen Susie Grant , Ko Ryan B. , Shin June Ho , Maxim Peter G. , Lui Natalie S. , Backhus Leah M. , Berry Mark F. , Shrager Joseph B. , Ramchandran Kavitha J. , Padda Sukhmani K. , Das Millie , Neal Joel W. , Wakelee Heather A. , Alizadeh Ash A. , Loo Billy W. , Diehn Maximilian
Published: March 2024

Abstract
Tumor genotyping is not routinely performed in localized non–small cell lung cancer (NSCLC) due to lack of associations of mutations with outcome. Here, we analyze 232 consecutive patients with localized NSCLC and demonstrate that KEAP1 and NFE2L2 mutations are predictive of high rates of local recurrence (LR) after radiotherapy but not surgery. Half of LRs occurred in tumors with KEAP1/NFE2L2 mutations, indicating that they are major molecular drivers of clinical radioresistance. Next, we functionally evaluate KEAP1/NFE2L2 mutations in our radiotherapy cohort and demonstrate that only pathogenic mutations are associated with radioresistance. Furthermore, expression of NFE2L2 target genes does not predict LR, underscoring the utility of tumor genotyping. Finally, we show that glutaminase inhibition preferentially radiosensitizes KEAP1-mutant cells via depletion of glutathione and increased radiation-induced DNA damage. Our findings suggest that genotyping for KEAP1/NFE2L2 mutations could facilitate treatment personalization and provide a potential strategy for overcoming radioresistance conferred by these mutations.
Significance:
This study shows that mutations in KEAP1 and NFE2L2 predict for LR after radiotherapy but not surgery in patients with NSCLC. Approximately half of all LRs are associated with these mutations and glutaminase inhibition may allow personalized radiosensitization of KEAP1/NFE2L2-mutant tumors.

This article is highlighted in the In This Issue feature, p. 1775
Data from The Evolutionary Origins of Recurrent Pancreatic Cancer
Authors: Sakamoto Hitomi , Attiyeh Marc A. , Gerold Jeffrey M. , Makohon-Moore Alvin P. , Hayashi Akimasa , Hong Jungeui , Kappagantula Rajya , Zhang Lance , Melchor Jerry P. , Reiter Johannes G. , Heyde Alexander , Bielski Craig M. , Penson Alexander V. , Gönen Mithat , Chakravarty Debyani , O'Reilly Eileen M. , Wood Laura D. , Hruban Ralph H. , Nowak Martin A. , Socci Nicholas D. , Taylor Barry S. , Iacobuzio-Donahue Christine A.
Published: March 2024

Abstract
Surgery is the only curative option for stage I/II pancreatic cancer; nonetheless, most patients will experience a recurrence after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer, we performed whole-exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that recurrent disease after adjuvant or first-line platinum therapy corresponds to an increased mutational burden. Recurrent disease is enriched for genetic alterations predicted to activate MAPK/ERK and PI3K–AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment-induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In 1 patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings suggest routine post-treatment sampling may have value in the management of recurrent pancreatic cancer.
Significance:
The biological features or clinical vulnerabilities of recurrent pancreatic cancer after pancreaticoduodenectomy are unknown. Using whole-exome sequencing we find that recurrent disease has a distinct genomic landscape, intermetastatic genetic heterogeneity, diverse clonal origins, and higher mutational burden than found for treatment-naïve disease.

See related commentary by Bednar and Pasca di Magliano, p. 762.

This article is highlighted in the In This Issue feature, p. 747
Data from Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma
Authors: Mondello Patrizia , Tadros Saber , Teater Matt , Fontan Lorena , Chang Aaron Y. , Jain Neeraj , Yang Haopeng , Singh Shailbala , Ying Hsia-Yuan , Chu Chi-Shuen , Ma Man Chun John , Toska Eneda , Alig Stefan , Durant Matthew , de Stanchina Elisa , Ghosh Sreejoyee , Mottok Anja , Nastoupil Loretta , Neelapu Sattva S. , Weigert Oliver , Inghirami Giorgio , Baselga José , Younes Anas , Yee Cassian , Dogan Ahmet , Scheinberg David A. , Roeder Robert G. , Melnick Ari M. , Green Michael R.
Published: March 2024

Abstract
CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6–HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse CREBBP-mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II–dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas.
Significance:
We have leveraged the molecular characterization of different types of CREBBP mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBP-mutant cells in tandem with promoting antitumor immunity.

This article is highlighted in the In This Issue feature, p. 327
Data from Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer
Authors: Fong Lawrence , Hotson Andrew , Powderly John D. , Sznol Mario , Heist Rebecca S. , Choueiri Toni K. , George Saby , Hughes Brett G.M. , Hellmann Matthew D. , Shepard Dale R. , Rini Brian I. , Kummar Shivaani , Weise Amy M. , Riese Matthew J. , Markman Ben , Emens Leisha A. , Mahadevan Daruka , Luke Jason J. , Laport Ginna , Brody Joshua D. , Hernandez-Aya Leonel , Bonomi Philip , Goldman Jonathan W. , Berim Lyudmyla , Renouf Daniel J. , Goodwin Rachel A. , Munneke Brian , Ho Po Y. , Hsieh Jessica , McCaffery Ian , Kwei Long , Willingham Stephen B. , Miller Richard A.
Published: March 2024

Abstract
Adenosine mediates immunosuppression within the tumor microenvironment through triggering adenosine 2A receptors (A2AR) on immune cells. To determine whether this pathway could be targeted as an immunotherapy, we performed a phase I clinical trial with a small-molecule A2AR antagonist. We find that this molecule can safely block adenosine signaling in vivo. In a cohort of 68 patients with renal cell cancer (RCC), we also observe clinical responses alone and in combination with an anti–PD-L1 antibody, including subjects who had progressed on PD-1/PD-L1 inhibitors. Durable clinical benefit is associated with increased recruitment of CD8+ T cells into the tumor. Treatment can also broaden the circulating T-cell repertoire. Clinical responses are associated with an adenosine-regulated gene-expression signature in pretreatment tumor biopsies. A2AR signaling, therefore, represents a targetable immune checkpoint distinct from PD-1/PD-L1 that restricts antitumor immunity.
Significance:
This first-in-human study of an A2AR antagonist for cancer treatment establishes the safety and feasibility of targeting this pathway by demonstrating antitumor activity with single-agent and anti–PD-L1 combination therapy in patients with refractory RCC. Responding patients possess an adenosine-regulated gene-expression signature in pretreatment tumor biopsies.

See related commentary by Sitkovsky, p. 16.

This article is highlighted in the In This Issue feature, p. 1
Data from Golgi Acidification by NHE7 Regulates Cytosolic pH Homeostasis in Pancreatic Cancer Cells
Authors: Galenkamp Koen M.O. , Sosicka Paulina , Jung Michael , Recouvreux M. Victoria , Zhang Yijuan , Moldenhauer Matthew R. , Brandi Giovanni , Freeze Hudson H. , Commisso Cosimo
Published: March 2024

Abstractabstract
Cancer cells reprogram their metabolism to meet elevated energy demands and favor glycolysis for energy production. This boost in glycolytic flux supports proliferation, but also generates acid in the form of hydrogen ions that must be eliminated from the cytoplasm to maintain the alkaline intracellular pH (pHi) associated with transformation. To cope with acid production, tumor cells employ ion transport systems, including the family of sodium–hydrogen exchangers (NHE). Here, we identify NHE7 as a novel regulator of pHi in pancreatic ductal adenocarcinoma (PDAC). We determine that NHE7 suppression causes alkalinization of the Golgi, leading to a buildup of cytosolic acid that diminishes tumor cell fitness mainly through the dysregulation of actin. Importantly, NHE7 knockdown in vivo leads to the abrogation of tumor growth. These results identify Golgi acidification as a mechanism to control pHi and point to the regulation of pHi as a possible therapeutic vulnerability in PDAC.
Significance:
NHE7 regulates cytosolic pH through Golgi acidification, which points to the Golgi as a “proton sink” for metabolic acid. Disruption of cytosolic pH homeostasis via NHE7 suppression compromises PDAC cell viability and tumor growth.

See related commentary by Ward and DeNicola, p. 768.

This article is highlighted in the In This Issue feature, p. 747
Data from The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients
Authors: Hallin Jill , Engstrom Lars D. , Hargis Lauren , Calinisan Andrew , Aranda Ruth , Briere David M. , Sudhakar Niranjan , Bowcut Vickie , Baer Brian R. , Ballard Joshua A. , Burkard Michael R. , Fell Jay B. , Fischer John P. , Vigers Guy P. , Xue Yaohua , Gatto Sole , Fernandez-Banet Julio , Pavlicek Adam , Velastagui Karen , Chao Richard C. , Barton Jeremy , Pierobon Mariaelena , Baldelli Elisa , Patricoin Emanuel F. , Cassidy Douglas P. , Marx Matthew A. , Rybkin Igor I. , Johnson Melissa L. , Ou Sai-Hong Ignatius , Lito Piro , Papadopoulos Kyriakos P. , Jänne Pasi A. , Olson Peter , Christensen James G.
Published: March 2024

Abstract
Despite decades of research, efforts to directly target KRAS have been challenging. MRTX849 was identified as a potent, selective, and covalent KRASG12C inhibitor that exhibits favorable drug-like properties, selectively modifies mutant cysteine 12 in GDP-bound KRASG12C, and inhibits KRAS-dependent signaling. MRTX849 demonstrated pronounced tumor regression in 17 of 26 (65%) KRASG12C-positive cell line– and patient-derived xenograft models from multiple tumor types, and objective responses have been observed in patients with KRASG12C-positive lung and colon adenocarcinomas. Comprehensive pharmacodynamic and pharmacogenomic profiling in sensitive and partially resistant nonclinical models identified mechanisms implicated in limiting antitumor activity including KRAS nucleotide cycling and pathways that induce feedback reactivation and/or bypass KRAS dependence. These factors included activation of receptor tyrosine kinases (RTK), bypass of KRAS dependence, and genetic dysregulation of cell cycle. Combinations of MRTX849 with agents that target RTKs, mTOR, or cell cycle demonstrated enhanced response and marked tumor regression in several tumor models, including MRTX849-refractory models.
Significance:
The discovery of MRTX849 provides a long-awaited opportunity to selectively target KRASG12C in patients. The in-depth characterization of MRTX849 activity, elucidation of response and resistance mechanisms, and identification of effective combinations provide new insight toward KRAS dependence and the rational development of this class of agents.

See related commentary by Klempner and Hata, p. 20.

This article is highlighted in the In This Issue feature, p. 1
Data from Circadian Regulator CLOCK Recruits Immune-Suppressive Microglia into the GBM Tumor Microenvironment
Authors: Chen Peiwen , Hsu Wen-Hao , Chang Andrew , Tan Zhi , Lan Zhengdao , Zhou Ashley , Spring Denise J. , Lang Frederick F. , Wang Y. Alan , DePinho Ronald A.
Published: March 2024

Abstract
Glioblastoma (GBM) is a lethal brain tumor containing a subpopulation of glioma stem cells (GSC). Pan-cancer analyses have revealed that stemness of cancer cells correlates positively with immunosuppressive pathways in many solid tumors, including GBM, prompting us to conduct a gain-of-function screen of epigenetic regulators that may influence GSC self-renewal and tumor immunity. The circadian regulator CLOCK emerged as a top hit in enhancing stem-cell self-renewal, which was amplified in about 5% of human GBM cases. CLOCK and its heterodimeric partner BMAL1 enhanced GSC self-renewal and triggered protumor immunity via transcriptional upregulation of OLFML3, a novel chemokine recruiting immune-suppressive microglia into the tumor microenvironment. In GBM models, CLOCK or OLFML3 depletion reduced intratumoral microglia density and extended overall survival. We conclude that the CLOCK–BMAL1 complex contributes to key GBM hallmarks of GSC maintenance and immunosuppression and, together with its downstream target OLFML3, represents new therapeutic targets for this disease.
Significance:
Circadian regulator CLOCK drives GSC self-renewal and metabolism and promotes microglia infiltration through direct regulation of a novel microglia-attracting chemokine, OLFML3. CLOCK and/or OLFML3 may represent novel therapeutic targets for GBM.

This article is highlighted in the In This Issue feature, p. 327
Data from Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)
Authors: Diab Adi , Tannir Nizar M. , Bentebibel Salah-Eddine , Hwu Patrick , Papadimitrakopoulou Vassiliki , Haymaker Cara , Kluger Harriet M. , Gettinger Scott N. , Sznol Mario , Tykodi Scott S. , Curti Brendan D. , Tagliaferri Mary A. , Zalevsky Jonathan , Hannah Alison L. , Hoch Ute , Aung Sandra , Fanton Christie , Rizwan Ahsan , Iacucci Ernesto , Liao Yijie , Bernatchez Chantale , Hurwitz Michael E. , Cho Daniel C.
Published: March 2024

Abstract
This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non–small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension (n = 1), hyperglycemia (n = 1), metabolic acidosis (n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8+ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status.
Significance:
These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade.

See related commentary by Rouanne et al., p. 1097.

This article is highlighted in the In This Issue feature, p. 1079
Data from Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers
Authors: Parkhurst Maria R. , Robbins Paul F. , Tran Eric , Prickett Todd D. , Gartner Jared J. , Jia Li , Ivey Gabriel , Li Yong F. , El-Gamil Mona , Lalani Almin , Crystal Jessica S. , Sachs Abraham , Groh Eric , Ray Satyajit , Ngo Lien T. , Kivitz Scott , Pasetto Anna , Yossef Rami , Lowery Frank J. , Goff Stephanie L. , Lo Winifred , Cafri Gal , Deniger Drew C. , Malekzadeh Parisa , Ahmadzadeh Mojgan , Wunderlich John R. , Somerville Robert P.T. , Rosenberg Steven A.
Published: March 2024

Abstract
Immunotherapies can mediate regression of human tumors with high mutation rates, but responses are rarely observed in patients with common epithelial cancers. This raises the question of whether patients with these common cancers harbor T lymphocytes that recognize mutant proteins expressed by autologous tumors that may represent ideal targets for immunotherapy. Using high-throughput immunologic screening of mutant gene products identified via whole-exome sequencing, we identified neoantigen-reactive tumor-infiltrating lymphocytes (TIL) from 62 of 75 (83%) patients with common gastrointestinal cancers. In total, 124 neoantigen-reactive TIL populations were identified, and all but one of the neoantigenic determinants were unique. The results of in vitro T-cell recognition assays demonstrated that 1.6% of the gene products encoded by somatic nonsynonymous mutations were immunogenic. These findings demonstrate that the majority of common epithelial cancers elicit immune recognition and open possibilities for cell-based immunotherapies for patients bearing these cancers.
Significance:
TILs cultured from 62 of 75 (83%) patients with gastrointestinal cancers recognized neoantigens encoded by 1.6% of somatic mutations expressed by autologous tumor cells, and 99% of the neoantigenic determinants appeared to be unique and not shared between patients.

This article is highlighted in the In This Issue feature, p. 983
Data from Inactivation of Fbxw7 Impairs dsRNA Sensing and Confers Resistance to PD-1 Blockade
Authors: Gstalder Cécile , Liu David , Miao Diana , Lutterbach Bart , DeVine Alexander L. , Lin Chenyu , Shettigar Megha , Pancholi Priya , Buchbinder Elizabeth I. , Carter Scott L. , Manos Michael P. , Rojas-Rudilla Vanesa , Brennick Ryan , Gjini Evisa , Chen Pei-Hsuan , Lako Ana , Rodig Scott , Yoon Charles H. , Freeman Gordon J. , Barbie David A. , Hodi F. Stephen , Miles Wayne , Van Allen Eliezer M. , Haq Rizwan
Published: March 2024

Abstract
The molecular mechanisms leading to resistance to PD-1 blockade are largely unknown. Here, we characterize tumor biopsies from a patient with melanoma who displayed heterogeneous responses to anti–PD-1 therapy. We observe that a resistant tumor exhibited a loss-of-function mutation in the tumor suppressor gene FBXW7, whereas a sensitive tumor from the same patient did not. Consistent with a functional role in immunotherapy response, inactivation of Fbxw7 in murine tumor cell lines caused resistance to anti–PD-1 in immunocompetent animals. Loss of Fbxw7 was associated with altered immune microenvironment, decreased tumor-intrinsic expression of the double-stranded RNA (dsRNA) sensors MDA5 and RIG-I, and diminished induction of type I IFN and MHC-I expression. In contrast, restoration of dsRNA sensing in Fbxw7-deficient cells was sufficient to sensitize them to anti–PD-1. Our results thus establish a new role for the commonly inactivated tumor suppressor FBXW7 in viral sensing and sensitivity to immunotherapy.
Significance:
Our findings establish a role of the commonly inactivated tumor suppressor FBXW7 as a genomic driver of response to anti–PD-1 therapy. Fbxw7 loss promotes resistance to anti–PD-1 through the downregulation of viral sensing pathways, suggesting that therapeutic reactivation of these pathways could improve clinical responses to checkpoint inhibitors in genomically defined cancer patient populations.

This article is highlighted in the In This Issue feature, p. 1241
Data from Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition
Authors: Cai Sheng F. , Chu S. Haihua , Goldberg Aaron D. , Parvin Salma , Koche Richard P. , Glass Jacob L. , Stein Eytan M. , Tallman Martin S. , Sen Filiz , Famulare Christopher A. , Cusan Monica , Huang Chun-Hao , Chen Chun-Wei , Zou Lihua , Cordner Keith B. , DelGaudio Nicole L. , Durani Vidushi , Kini Mitali , Rex Madison , Tian Helen S. , Zuber Johannes , Baslan Timour , Lowe Scott W. , Rienhoff Hugh Y. , Letai Anthony , Levine Ross L. , Armstrong Scott A.
Published: March 2024

Abstract
The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin–driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor MECOM (EVI1) compared with leukemias derived from myeloid progenitors. Here, we compared leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for EVI1 in modulating p53 protein abundance and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 (LSD1) inhibitors in addition to classical genotoxic stresses. p53 loss of function in Evi1lo progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1hi leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant EVI1hi acute myeloid leukemia.
Significance:
We demonstrate that the cell of origin of leukemia initiation influences p53 activity and dictates therapeutic sensitivity to pharmacologic LSD1 inhibitors via the transcription factor EVI1. We show that drug resistance could be overcome in HSC-derived leukemias by combining LSD1 inhibition with venetoclax.

See related commentary by Gu et al., p. 1445.

This article is highlighted in the In This Issue feature, p. 1426
Data from Timed Ang2-Targeted Therapy Identifies the Angiopoietin–Tie Pathway as Key Regulator of Fatal Lymphogenous Metastasis
Authors: Gengenbacher Nicolas , Singhal Mahak , Mogler Carolin , Hai Ling , Milde Laura , Pari Ashik Ahmed Abdul , Besemfelder Eva , Fricke Claudine , Baumann Daniel , Gehrs Stephanie , Utikal Jochen , Felcht Moritz , Hu Junhao , Schlesner Matthias , Offringa Rienk , Chintharlapalli Sudhakar R. , Augustin Hellmut G.
Published: March 2024

Abstract
Recent clinical and preclinical advances have highlighted the existence of a previously hypothesized lymphogenous route of metastasis. However, due to a lack of suitable preclinical modeling tools, its contribution to long-term disease outcome and relevance for therapy remain controversial. Here, we established a genetically engineered mouse model (GEMM) fragment–based tumor model uniquely sustaining a functional network of intratumoral lymphatics that facilitates seeding of fatal peripheral metastases. Multiregimen survival studies and correlative patient data identified primary tumor–derived Angiopoietin-2 (Ang2) as a potent therapeutic target to restrict lymphogenous tumor cell dissemination. Mechanistically, tumor-associated lymphatic endothelial cells (EC), in contrast to blood vascular EC, were found to be critically addicted to the Angiopoietin–Tie pathway. Genetic manipulation experiments in combination with single-cell mapping revealed agonistically acting Ang2–Tie2 signaling as key regulator of lymphatic maintenance. Correspondingly, acute presurgical Ang2 neutralization was sufficient to prolong survival by regressing established intratumoral lymphatics, hence identifying a therapeutic regimen that warrants further clinical evaluation.
Significance:
Exploiting multiple mouse tumor models including a unique GEMM-derived allograft system in combination with preclinical therapy designs closely matching the human situation, this study provides fundamental insight into the biology of tumor-associated lymphatic EC and defines an innovative presurgical therapeutic window of migrastatic Ang2 neutralization to restrict lymphogenous metastasis.

This article is highlighted in the In This Issue feature, p. 211
Data from Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Correlates of Response and Mechanisms of Resistance to Pemigatinib
Authors: Silverman Ian M. , Hollebecque Antoine , Friboulet Luc , Owens Sherry , Newton Robert C. , Zhen Huiling , Féliz Luis , Zecchetto Camilla , Melisi Davide , Burn Timothy C.
Published: March 2024

Abstract
Pemigatinib, a selective FGFR1–3 inhibitor, has demonstrated antitumor activity in FIGHT-202, a phase II study in patients with cholangiocarcinoma harboring FGFR2 fusions/rearrangements, and has gained regulatory approval in the United States. Eligibility for FIGHT-202 was assessed using genomic profiling; here, these data were utilized to characterize the genomic landscape of cholangiocarcinoma and to uncover unique molecular features of patients harboring FGFR2 rearrangements. The results highlight the high percentage of patients with cholangiocarcinoma harboring potentially actionable genomic alterations and the diversity in gene partners that rearrange with FGFR2. Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance. Genomic subsets of patients with other potentially actionable FGF/FGFR alterations were also identified. Our study provides a framework for molecularly guided clinical trials and underscores the importance of genomic profiling to enable a deeper understanding of the molecular basis for response and nonresponse to targeted therapy.
Significance:
We utilized genomic profiling data from FIGHT-202 to gain insights into the genomic landscape of cholangiocarcinoma, to understand the molecular diversity of patients with FGFR2 fusions or rearrangements, and to interrogate the clinicogenomics of patients treated with pemigatinib. Our study highlights the utility of genomic profiling in clinical trials.

This article is highlighted in the In This Issue feature, p. 211
Data from RBMS1 Suppresses Colon Cancer Metastasis through Targeted Stabilization of Its mRNA Regulon
Authors: Yu Johnny , Navickas Albertas , Asgharian Hosseinali , Culbertson Bruce , Fish Lisa , Garcia Kristle , Olegario John Paolo , Dermit Maria , Dodel Martin , Hänisch Benjamin , Luo Yikai , Weinberg Ethan M. , Dienstmann Rodrigo , Warren Robert S. , Mardakheh Faraz K. , Goodarzi Hani
Published: March 2024

Abstract
Identifying master regulators that drive pathologic gene expression is a key challenge in precision oncology. Here, we have developed an analytic framework, named PRADA, that identifies oncogenic RNA-binding proteins through the systematic detection of coordinated changes in their target regulons. Application of this approach to data collected from clinical samples, patient-derived xenografts, and cell line models of colon cancer metastasis revealed the RNA-binding protein RBMS1 as a suppressor of colon cancer progression. We observed that silencing RBMS1 results in increased metastatic capacity in xenograft mouse models, and that restoring its expression blunts metastatic liver colonization. We have found that RBMS1 functions as a posttranscriptional regulator of RNA stability by directly binding its target mRNAs. Together, our findings establish a role for RBMS1 as a previously unknown regulator of RNA stability and as a suppressor of colon cancer metastasis with clinical utility for risk stratification of patients.
Significance:
By applying a new analytic approach to transcriptomic data from clinical samples and models of colon cancer progression, we have identified RBMS1 as a suppressor of metastasis and as a post-transcriptional regulator of RNA stability. Notably, RBMS1 silencing and downregulation of its targets are negatively associated with patient survival.

See related commentary by Carter, p. 1261.

This article is highlighted in the In This Issue feature, p. 1241
Data from First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematologic Cancers: Results of a Phase I Dose-Escalation Study
Authors: Khot Amit , Brajanovski Natalie , Cameron Donald P. , Hein Nadine , Maclachlan Kylee H. , Sanij Elaine , Lim John , Soong John , Link Emma , Blombery Piers , Thompson Ella R. , Fellowes Andrew , Sheppard Karen E. , McArthur Grant A. , Pearson Richard B. , Hannan Ross D. , Poortinga Gretchen , Harrison Simon J.
Published: March 2024

Abstract
RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) is tightly regulated downstream of oncogenic pathways, and its dysregulation is a common feature in cancer. We evaluated CX-5461, the first-in-class selective rDNA transcription inhibitor, in a first-in-human, phase I dose-escalation study in advanced hematologic cancers. Administration of CX-5461 intravenously once every 3 weeks to 5 cohorts determined an MTD of 170 mg/m2, with a predictable pharmacokinetic profile. The dose-limiting toxicity was palmar–plantar erythrodysesthesia; photosensitivity was a dose-independent adverse event (AE), manageable by preventive measures. CX-5461 induced rapid on-target inhibition of rDNA transcription, with p53 activation detected in tumor cells from one patient achieving a clinical response. One patient with anaplastic large cell lymphoma attained a prolonged partial response and 5 patients with myeloma and diffuse large B-cell lymphoma achieved stable disease as best response. CX-5461 is safe at doses associated with clinical benefit and dermatologic AEs are manageable.
Significance:
CX-5461 is a first-in-class selective inhibitor of rDNA transcription. This first-in-human study establishes the feasibility of targeting this process, demonstrating single-agent antitumor activity against advanced hematologic cancers with predictable pharmacokinetics and a safety profile allowing prolonged dosing. Consistent with preclinical data, antitumor activity was observed in TP53 wild-type and mutant malignancies.

This article is highlighted in the In This Issue feature, p. 983