bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from PTEN Regulates Glutamine Flux to Pyrimidine Synthesis and Sensitivity to Dihydroorotate Dehydrogenase Inhibition
Authors: Mathur Deepti , Stratikopoulos Elias , Ozturk Sait , Steinbach Nicole , Pegno Sarah , Schoenfeld Sarah , Yong Raymund , Murty Vundavalli V. , Asara John M. , Cantley Lewis C. , Parsons Ramon
Published: March 2024

Abstract
Metabolic changes induced by oncogenic drivers of cancer contribute to tumor growth and are attractive targets for cancer treatment. Here, we found that increased growth of PTEN-mutant cells was dependent on glutamine flux through the de novo pyrimidine synthesis pathway, which created sensitivity to the inhibition of dihydroorotate dehydrogenase, a rate-limiting enzyme for pyrimidine ring synthesis. S-phase PTEN-mutant cells showed increased numbers of replication forks, and inhibitors of dihydroorotate dehydrogenase led to chromosome breaks and cell death due to inadequate ATR activation and DNA damage at replication forks. Our findings indicate that enhanced glutamine flux generates vulnerability to dihydroorotate dehydrogenase inhibition, which then causes synthetic lethality in PTEN-deficient cells due to inherent defects in ATR activation. Inhibition of dihydroorotate dehydrogenase could thus be a promising therapy for patients with PTEN-mutant cancers.

Significance: We have found a prospective targeted therapy for PTEN-deficient tumors, with efficacy in vitro and in vivo in tumors derived from different tissues. This is based upon the changes in glutamine metabolism, DNA replication, and DNA damage response which are consequences of inactivation of PTEN. Cancer Discov; 7(4); 380–90. ©2017 AACR.

See related article by Brown et al., p. 391.

This article is highlighted in the In This Issue feature, p. 339
Data from Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors
Authors: Juric Dejan , Krop Ian , Ramanathan Ramesh K. , Wilson Timothy R. , Ware Joseph A. , Sanabria Bohorquez Sandra M. , Savage Heidi M. , Sampath Deepak , Salphati Laurent , Lin Ray S. , Jin Huan , Parmar Hema , Hsu Jerry Y. , Von Hoff Daniel D. , Baselga José
Published: March 2024

Abstract
Taselisib is a potent and selective tumor growth inhibitor through PI3K pathway suppression. Thirty-four patients with locally advanced or metastatic solid tumors were treated (phase I study, modified 3+3 dose escalation; 5 cohorts; 3–16 mg taselisib once-daily capsule). Taselisib pharmacokinetics were dose-proportional; mean half-life was 40 hours. Frequent dose-dependent, treatment-related adverse events included diarrhea, hyperglycemia, decreased appetite, nausea, rash, stomatitis, and vomiting. At 12 and 16 mg dose levels, dose-limiting toxicities (DLT) were observed, with an accumulation of higher-grade adverse events after the cycle 1 DLT assessment window. Pharmacodynamic findings showed pathway inhibition at ≥3 mg in patient tumor samples, consistent with preclinical PIK3CA-mutant tumor xenograft models. Confirmed response rate was 36% for PIK3CA-mutant tumor patients with measurable disease [5/14: 4 breast cancer (3 patients at 12 mg); 1 non–small cell lung cancer], where responses started at 3 mg, and 0% in patients with tumors without known PIK3CA hotspot mutations (0/15).

Significance: Preliminary data consistent with preclinical data indicate increased antitumor activity of taselisib in patients with PIK3CA-mutant tumors (in comparison with patients with tumors without known activating PIK3CA hotspot mutations) starting at the lowest dose tested of 3 mg, thereby supporting higher potency for taselisib against PIK3CA-mutant tumors. Cancer Discov; 7(7); 704–15. ©2017 AACR.

See related commentary by Rodon and Tabernero, p. 666.

This article is highlighted in the In This Issue feature, p. 653
Data from Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma
Authors: Grommes Christian , Pastore Alessandro , Palaskas Nicolaos , Tang Sarah S. , Campos Carl , Schartz Derrek , Codega Paolo , Nichol Donna , Clark Owen , Hsieh Wan-Ying , Rohle Dan , Rosenblum Marc , Viale Agnes , Tabar Viviane S. , Brennan Cameron W. , Gavrilovic Igor T. , Kaley Thomas J. , Nolan Craig P. , Omuro Antonio , Pentsova Elena , Thomas Alissa A. , Tsyvkin Elina , Noy Ariela , Palomba M. Lia , Hamlin Paul , Sauter Craig S. , Moskowitz Craig H. , Wolfe Julia , Dogan Ahmet , Won Minhee , Glass Jon , Peak Scott , Lallana Enrico C. , Hatzoglou Vaios , Reiner Anne S. , Gutin Philip H. , Huse Jason T. , Panageas Katherine S. , Graeber Thomas G. , Schultz Nikolaus , DeAngelis Lisa M. , Mellinghoff Ingo K.
Published: March 2024

Abstract
Bruton tyrosine kinase (BTK) links the B-cell antigen receptor (BCR) and Toll-like receptors with NF-κB. The role of BTK in primary central nervous system (CNS) lymphoma (PCNSL) is unknown. We performed a phase I clinical trial with ibrutinib, the first-in-class BTK inhibitor, for patients with relapsed or refractory CNS lymphoma. Clinical responses to ibrutinib occurred in 10 of 13 (77%) patients with PCNSL, including five complete responses. The only PCNSL with complete ibrutinib resistance harbored a mutation within the coiled-coil domain of CARD11, a known ibrutinib resistance mechanism. Incomplete tumor responses were associated with mutations in the B-cell antigen receptor–associated protein CD79B. CD79B-mutant PCNSLs showed enrichment of mammalian target of rapamycin (mTOR)-related gene sets and increased staining with PI3K/mTOR activation markers. Inhibition of the PI3K isoforms p110α/p110δ or mTOR synergized with ibrutinib to induce cell death in CD79B-mutant PCNSL cells.

Significance: Ibrutinib has substantial activity in patients with relapsed or refractory B-cell lymphoma of the CNS. Response rates in PCNSL were considerably higher than reported for diffuse large B-cell lymphoma outside the CNS, suggesting a divergent molecular pathogenesis. Combined inhibition of BTK and PI3K/mTOR may augment the ibrutinib response in CD79B-mutant human PCNSLs. Cancer Discov; 7(9); 1018–29. ©2017 AACR.

See related commentary by Lakshmanan and Byrd, p. 940.

This article is highlighted in the In This Issue feature, p. 920
Data from Adaptive Reprogramming of De Novo Pyrimidine Synthesis Is a Metabolic Vulnerability in Triple-Negative Breast Cancer
Authors: Brown Kristin K. , Spinelli Jessica B. , Asara John M. , Toker Alex
Published: March 2024

Abstract
Chemotherapy resistance is a major barrier to the treatment of triple-negative breast cancer (TNBC), and strategies to circumvent resistance are required. Using in vitro and in vivo metabolic profiling of TNBC cells, we show that an increase in the abundance of pyrimidine nucleotides occurs in response to chemotherapy exposure. Mechanistically, elevation of pyrimidine nucleotides induced by chemotherapy is dependent on increased activity of the de novo pyrimidine synthesis pathway. Pharmacologic inhibition of de novo pyrimidine synthesis sensitizes TNBC cells to genotoxic chemotherapy agents by exacerbating DNA damage. Moreover, combined treatment with doxorubicin and leflunomide, a clinically approved inhibitor of the de novo pyrimidine synthesis pathway, induces regression of TNBC xenografts. Thus, the increase in pyrimidine nucleotide levels observed following chemotherapy exposure represents a metabolic vulnerability that can be exploited to enhance the efficacy of chemotherapy for the treatment of TNBC.

Significance: The prognosis for patients with TNBC with residual disease after chemotherapy is poor. We find that chemotherapy agents induce adaptive reprogramming of de novo pyrimidine synthesis and show that this response can be exploited pharmacologically, using clinically approved inhibitors of de novo pyrimidine synthesis, to sensitize TNBC cells to chemotherapy. Cancer Discov; 7(4); 391–9. ©2017 AACR.

See related article by Mathur et al., p. 380.

This article is highlighted in the In This Issue feature, p. 339
Data from PAX3–FOXO1 Establishes Myogenic Super Enhancers and Confers BET Bromodomain Vulnerability
Authors: Gryder Berkley E. , Yohe Marielle E. , Chou Hsien-Chao , Zhang Xiaohu , Marques Joana , Wachtel Marco , Schaefer Beat , Sen Nirmalya , Song Young , Gualtieri Alberto , Pomella Silvia , Rota Rossella , Cleveland Abigail , Wen Xinyu , Sindiri Sivasish , Wei Jun S. , Barr Frederic G. , Das Sudipto , Andresson Thorkell , Guha Rajarshi , Lal-Nag Madhu , Ferrer Marc , Shern Jack F. , Zhao Keji , Thomas Craig J. , Khan Javed
Published: March 2024

Abstract
Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3–FOXO1. The mechanisms by which PAX3–FOXO1 dysregulates chromatin are unknown. We find PAX3–FOXO1 reprograms the cis-regulatory landscape by inducing de novo super enhancers. PAX3–FOXO1 uses super enhancers to set up autoregulatory loops in collaboration with the master transcription factors MYOG, MYOD, and MYCN. This myogenic super enhancer circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small-molecule inhibition of protein targets induced by, or bound to, PAX3–FOXO1-occupied super enhancers. Furthermore, PAX3–FOXO1 recruits and requires the BET bromodomain protein BRD4 to function at super enhancers, resulting in a complete dependence on BRD4 and a significant susceptibility to BRD inhibition. These results yield insights into the epigenetic functions of PAX3–FOXO1 and reveal a specific vulnerability that can be exploited for precision therapy.

Significance: PAX3–FOXO1 drives pediatric fusion-positive rhabdomyosarcoma, and its chromatin-level functions are critical to understanding its oncogenic activity. We find that PAX3–FOXO1 establishes a myoblastic super enhancer landscape and creates a profound subtype-unique dependence on BET bromodomains, the inhibition of which ablates PAX3–FOXO1 function, providing a mechanistic rationale for exploring BET inhibitors for patients bearing PAX-fusion rhabdomyosarcoma. Cancer Discov; 7(8); 884–99. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 783
Data from The Genetic Basis of Hepatosplenic T-cell Lymphoma
Authors: McKinney Matthew , Moffitt Andrea B. , Gaulard Philippe , Travert Marion , De Leval Laurence , Nicolae Alina , Raffeld Mark , Jaffe Elaine S. , Pittaluga Stefania , Xi Liqiang , Heavican Tayla , Iqbal Javeed , Belhadj Karim , Delfau-Larue Marie Helene , Fataccioli Virginie , Czader Magdalena B. , Lossos Izidore S. , Chapman-Fredricks Jennifer R. , Richards Kristy L. , Fedoriw Yuri , Ondrejka Sarah L. , Hsi Eric D. , Low Lawrence , Weisenburger Dennis , Chan Wing C. , Mehta-Shah Neha , Horwitz Steven , Bernal-Mizrachi Leon , Flowers Christopher R. , Beaven Anne W. , Parihar Mayur , Baseggio Lucile , Parrens Marie , Moreau Anne , Sujobert Pierre , Pilichowska Monika , Evens Andrew M. , Chadburn Amy , Au-Yeung Rex K.H. , Srivastava Gopesh , Choi William W. L. , Goodlad John R. , Aurer Igor , Basic-Kinda Sandra , Gascoyne Randy D. , Davis Nicholas S. , Li Guojie , Zhang Jenny , Rajagopalan Deepthi , Reddy Anupama , Love Cassandra , Levy Shawn , Zhuang Yuan , Datta Jyotishka , Dunson David B. , Davé Sandeep S.
Published: March 2024

Abstract
Hepatosplenic T-cell lymphoma (HSTL) is a rare and lethal lymphoma; the genetic drivers of this disease are unknown. Through whole-exome sequencing of 68 HSTLs, we define recurrently mutated driver genes and copy-number alterations in the disease. Chromatin-modifying genes, including SETD2, INO80, and ARID1B, were commonly mutated in HSTL, affecting 62% of cases. HSTLs manifest frequent mutations in STAT5B (31%), STAT3 (9%), and PIK3CD (9%), for which there currently exist potential targeted therapies. In addition, we noted less frequent events in EZH2, KRAS, and TP53. SETD2 was the most frequently silenced gene in HSTL. We experimentally demonstrated that SETD2 acts as a tumor suppressor gene. In addition, we found that mutations in STAT5B and PIK3CD activate critical signaling pathways important to cell survival in HSTL. Our work thus defines the genetic landscape of HSTL and implicates gene mutations linked to HSTL pathogenesis and potential treatment targets.

Significance: We report the first systematic application of whole-exome sequencing to define the genetic basis of HSTL, a rare but lethal disease. Our work defines SETD2 as a tumor suppressor gene in HSTL and implicates genes including INO80 and PIK3CD in the disease. Cancer Discov; 7(4); 369–79. ©2017 AACR.

See related commentary by Yoshida and Weinstock, p. 352.

This article is highlighted in the In This Issue feature, p. 339
Data from Analysis of Circulating Cell-Free DNA Identifies Multiclonal Heterogeneity of BRCA2 Reversion Mutations Associated with Resistance to PARP Inhibitors
Authors: Quigley David , Alumkal Joshi J. , Wyatt Alexander W. , Kothari Vishal , Foye Adam , Lloyd Paul , Aggarwal Rahul , Kim Won , Lu Eric , Schwartzman Jacob , Beja Kevin , Annala Matti , Das Rajdeep , Diolaiti Morgan , Pritchard Colin , Thomas George , Tomlins Scott , Knudsen Karen , Lord Christopher J. , Ryan Charles , Youngren Jack , Beer Tomasz M. , Ashworth Alan , Small Eric J. , Feng Felix Y.
Published: March 2024

Abstract
Approximately 20% of metastatic prostate cancers harbor mutations in genes required for DNA repair by homologous recombination repair (HRR) such as BRCA2. HRR defects confer synthetic lethality to PARP inhibitors (PARPi) such as olaparib and talazoparib. In ovarian or breast cancers, olaparib resistance has been associated with HRR restoration, including by BRCA2 mutation reversion. Whether similar mechanisms operate in prostate cancer, and could be detected in liquid biopsies, is unclear. Here, we identify BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA (cfDNA) reveals reversion mutation heterogeneity not discernable from a single solid-tumor biopsy and potentially allows monitoring for the emergence of PARPi resistance.

Significance: The mechanisms of clinical resistance to PARPi in DNA repair–deficient prostate cancer have not been described. Here, we show BRCA2 reversion mutations in patients with prostate cancer with metastatic disease who developed resistance to talazoparib and olaparib. Furthermore, we show that PARPi resistance is highly multiclonal and that cfDNA allows monitoring for PARPi resistance. Cancer Discov; 7(9); 999–1005. ©2017 AACR.

See related commentary by Domchek, p. 937.

See related article by Kondrashova et al., p. 984.

See related article by Goodall et al., p. 1006.

This article is highlighted in the In This Issue feature, p. 920
Data from In Vivo Genetic Screens of Patient-Derived Tumors Revealed Unexpected Frailty of the Transformed Phenotype
Authors: Bossi Daniela , Cicalese Angelo , Dellino Gaetano I. , Luzi Lucilla , Riva Laura , D'Alesio Carolina , Diaferia Giuseppe R. , Carugo Alessandro , Cavallaro Elena , Piccioni Rossana , Barberis Massimo , Mazzarol Giovanni , Testori Alessandro , Punzi Simona , Pallavicini Isabella , Tosti Giulio , Giacó Luciano , Melloni Giorgio , Heffernan Timothy P. , Natoli Gioacchino , Draetta Giulio F. , Minucci Saverio , Pelicci PierGiuseppe , Lanfrancone Luisa
Published: March 2024

Abstract
The identification of genes maintaining cancer growth is critical to our understanding of tumorigenesis. We report the first in vivo genetic screen of patient-derived tumors, using metastatic melanomas and targeting 236 chromatin genes by expression of specific shRNA libraries. Our screens revealed unprecedented numerosity of genes indispensable for tumor growth (∼50% of tested genes) and unexpected functional heterogeneity among patients (<15% in common). Notably, these genes were not activated by somatic mutations in the same patients and are therefore distinguished from mutated cancer driver genes. We analyzed underlying molecular mechanisms of one of the identified genes, the Histone–lysine N-methyltransferase KMT2D, and showed that it promotes tumorigenesis by dysregulating a subset of transcriptional enhancers and target genes involved in cell migration. The assembly of enhancer genomic patterns by activated KMT2D was highly patient-specific, regardless of the identity of transcriptional targets, suggesting that KMT2D might be activated by distinct upstream signaling pathways.

Significance: Drug targeting of biologically relevant cancer-associated mutations is considered a critical strategy to control cancer growth. Our functional in vivo genetic screens of patient-derived tumors showed unprecedented numerosity and interpatient heterogeneity of genes that are essential for tumor growth, but not mutated, suggesting that multiple, patient-specific signaling pathways are activated in tumors. Cancer Discov; 6(6); 650–63. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 561
Data from Dual Inhibition of EGFR with Afatinib and Cetuximab in Kinase Inhibitor–Resistant EGFR-Mutant Lung Cancer with and without T790M Mutations
Authors: Janjigian Yelena Y. , Smit Egbert F. , Groen Harry J.M. , Horn Leora , Gettinger Scott , Camidge D. Ross , Riely Gregory J. , Wang Bushi , Fu Yali , Chand Vikram K. , Miller Vincent A. , Pao William
Published: March 2024

Abstract
EGFR-mutant lung cancers responsive to reversible EGFR inhibitors (gefitinib/erlotinib) develop acquired resistance, mediated by second-site EGFR T790M mutation in >50% of cases. Preclinically, afatinib (irreversible ErbB family blocker) plus cetuximab (anti-EGFR monoclonal antibody) overcomes T790M-mediated resistance. This phase Ib study combining afatinib and cetuximab enrolled heavily pretreated patients with advanced EGFR-mutant lung cancer and acquired resistance to erlotinib/gefitinib. Patients provided post–acquired-resistance tumor samples for profiling EGFR mutations. Among 126 patients, objective response rate (overall 29%) was comparable in T790M-positive and T790M-negative tumors (32% vs. 25%; P = 0.341). Median progression-free survival was 4.7 months (95% confidence interval, 4.3–6.4), and the median duration of confirmed objective response was 5.7 months (range, 1.8–24.4). Therapy-related grade 3/4 adverse events occurred in 44%/2% of patients. Afatinib–cetuximab demonstrated robust clinical activity and a manageable safety profile in EGFR-mutant lung cancers with acquired resistance to gefitinib or erlotinib, both with and without T790M mutations, warranting further investigation.

Significance: This article reports the results of a trial combining afatinib and cetuximab in patients with acquired resistance and details the first clinical proof-of-concept for the preclinical hypothesis that a significant proportion of tumors in patients with acquired resistance to gefitinib/erlotinib remain dependent on EGFR signaling for survival. Cancer Discov; 4(9); 1036–45. ©2014 AACR.

See related commentary by Gibbons and Byers, p. 991

This article is highlighted in the In This Issue feature, p. 973
Data from A Transposon Screen Identifies Loss of Primary Cilia as a Mechanism of Resistance to SMO Inhibitors
Authors: Zhao Xuesong , Pak Ekaterina , Ornell Kimberly J. , Pazyra-Murphy Maria F. , MacKenzie Ethan L. , Chadwick Emily J. , Ponomaryov Tatyana , Kelleher Joseph F. , Segal Rosalind A.
Published: March 2024

Abstract
Drug resistance poses a great challenge to targeted cancer therapies. In Hedgehog pathway–dependent cancers, the scope of mechanisms enabling resistance to SMO inhibitors is not known. Here, we performed a transposon mutagenesis screen in medulloblastoma and identified multiple modes of resistance. Surprisingly, mutations in ciliogenesis genes represent a frequent cause of resistance, and patient datasets indicate that cilia loss constitutes a clinically relevant category of resistance. Conventionally, primary cilia are thought to enable oncogenic Hedgehog signaling. Paradoxically, we find that cilia loss protects tumor cells from susceptibility to SMO inhibitors and maintains a “persister” state that depends on continuous low output of the Hedgehog program. Persister cells can serve as a reservoir for further tumor evolution, as additional alterations synergize with cilia loss to generate aggressive recurrent tumors. Together, our findings reveal patterns of resistance and provide mechanistic insights for the role of cilia in tumor evolution and drug resistance.

Significance: Using a transposon screen and clinical datasets, we identified mutations in ciliogenesis genes as a new class of resistance to SMO inhibitors. Mechanistically, cilia-mutant tumors can either grow slowly in a “persister” state or evolve and progress rapidly in an “aggressive” state. Cancer Discov; 7(12); 1436–49. ©2017 AACR.

See related commentary by Goranci-Buzhala et al., p. 1374.

This article is highlighted in the In This Issue feature, p. 1355
Data from Endothelial Activation and Blood–Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells
Authors: Gust Juliane , Hay Kevin A. , Hanafi Laïla-Aïcha , Li Daniel , Myerson David , Gonzalez-Cuyar Luis F. , Yeung Cecilia , Liles W. Conrad , Wurfel Mark , Lopez Jose A. , Chen Junmei , Chung Dominic , Harju-Baker Susanna , Özpolat Tahsin , Fink Kathleen R. , Riddell Stanley R. , Maloney David G. , Turtle Cameron J.
Published: March 2024

Abstract
Lymphodepletion chemotherapy followed by infusion of CD19-targeted chimeric antigen receptor–modified T (CAR-T) cells can be complicated by neurologic adverse events (AE) in patients with refractory B-cell malignancies. In 133 adults treated with CD19 CAR-T cells, we found that acute lymphoblastic leukemia, high CD19+ cells in bone marrow, high CAR-T cell dose, cytokine release syndrome, and preexisting neurologic comorbidities were associated with increased risk of neurologic AEs. Patients with severe neurotoxicity demonstrated evidence of endothelial activation, including disseminated intravascular coagulation, capillary leak, and increased blood–brain barrier (BBB) permeability. The permeable BBB failed to protect the cerebrospinal fluid from high concentrations of systemic cytokines, including IFNγ, which induced brain vascular pericyte stress and their secretion of endothelium-activating cytokines. Endothelial activation and multifocal vascular disruption were found in the brain of a patient with fatal neurotoxicity. Biomarkers of endothelial activation were higher before treatment in patients who subsequently developed grade ≥4 neurotoxicity.

Significance: We provide a detailed clinical, radiologic, and pathologic characterization of neurotoxicity after CD19 CAR-T cells, and identify risk factors for neurotoxicity. We show endothelial dysfunction and increased BBB permeability in neurotoxicity and find that patients with evidence of endothelial activation before lymphodepletion may be at increased risk of neurotoxicity. Cancer Discov; 7(12); 1404–19. ©2017 AACR.

See related commentary by Mackall and Miklos, p. 1371.

This article is highlighted in the In This Issue feature, p. 1355
Data from Combined BRAF, EGFR, and MEK Inhibition in Patients with BRAFV600E-Mutant Colorectal Cancer
Authors: Corcoran Ryan B. , André Thierry , Atreya Chloe E. , Schellens Jan H.M. , Yoshino Takayuki , Bendell Johanna C. , Hollebecque Antoine , McRee Autumn J. , Siena Salvatore , Middleton Gary , Muro Kei , Gordon Michael S. , Tabernero Josep , Yaeger Rona , O'Dwyer Peter J. , Humblet Yves , De Vos Filip , Jung A. Scott , Brase Jan C. , Jaeger Savina , Bettinger Severine , Mookerjee Bijoyesh , Rangwala Fatima , Van Cutsem Eric
Published: March 2024

Abstract
Although BRAF inhibitor monotherapy yields response rates >50% in BRAFV600-mutant melanoma, only approximately 5% of patients with BRAFV600E colorectal cancer respond. Preclinical studies suggest that the lack of efficacy in BRAFV600E colorectal cancer is due to adaptive feedback reactivation of MAPK signaling, often mediated by EGFR. This clinical trial evaluated BRAF and EGFR inhibition with dabrafenib (D) + panitumumab (P) ± MEK inhibition with trametinib (T) to achieve greater MAPK suppression and improved efficacy in 142 patients with BRAFV600E colorectal cancer. Confirmed response rates for D+P, D+T+P, and T+P were 10%, 21%, and 0%, respectively. Pharmacodynamic analysis of paired pretreatment and on-treatment biopsies found that efficacy of D+T+P correlated with increased MAPK suppression. Serial cell-free DNA analysis revealed additional correlates of response and emergence of KRAS and NRAS mutations on disease progression. Thus, targeting adaptive feedback pathways in BRAFV600E colorectal cancer can improve efficacy, but MAPK reactivation remains an important primary and acquired resistance mechanism.

Significance: This trial demonstrates that combined BRAF + EGFR + MEK inhibition is tolerable, with promising activity in patients with BRAFV600E colorectal cancer. Our findings highlight the MAPK pathway as a critical target in BRAFV600E colorectal cancer and the need to optimize strategies inhibiting this pathway to overcome both primary and acquired resistance. Cancer Discov; 8(4); 428–43. ©2018 AACR.

See related commentary by Janku, p. 389.

See related article by Hazar-Rethinam et al., p. 417.

This article is highlighted in the In This Issue feature, p. 371
Data from Naïve T-cell Deficits at Diagnosis and after Chemotherapy Impair Cell Therapy Potential in Pediatric Cancers
Authors: Das Rajat K. , Vernau Lauren , Grupp Stephan A. , Barrett David M.
Published: March 2024

Abstract
Translational data on chimeric antigen receptor (CAR) T-cell trials indicate that the presence of naïve T cells in the premanufacture product is important to clinical response and persistence. In anticipation of developing CAR trials for other tumors, we investigated the T-cell distribution from children with solid tumors and lymphomas at diagnosis and after every cycle of chemotherapy. We found that patients with T cells enriched for naïve and stem central memory cells expanded well in vitro, but the majority of tumor types showed chemotherapy-related depletion of early lineage cells with a corresponding decline in successful ex vivo stimulation response. Unexpectedly, many pediatric patients with solid tumors had low numbers of naïve T cells prior to any therapy. These data indicate the ex vivo manufacture of CAR T cells may need to be customized based on the nature of T cells available in each disease type.
Significance:
Cumulative chemotherapy cycles deplete naïve T cells in many pediatric cancer regimens, reducing expansion potential associated with successful adoptive cellular therapies. Naïve T-cell deficits can be seen at diagnosis as well, implying immune deficits that exist prior to chemotherapy, which may also affect the development of immune-based therapies.

See related commentary by Leick and Maus, p. 466.

This article is highlighted in the In This Issue feature, p. 453
Data from A Phase Ib Dose-Escalation and Expansion Study of the BCL2 Inhibitor Venetoclax Combined with Tamoxifen in ER and BCL2–Positive Metastatic Breast Cancer
Authors: Lok Sheau W. , Whittle James R. , Vaillant François , Teh Charis E. , Lo Louisa L. , Policheni Antonia N. , Bergin Alice R.T. , Desai Jayesh , Ftouni Sarah , Gandolfo Luke C. , Liew Danny , Liu He K. , Mann G. Bruce , Moodie Kate , Murugasu Anand , Pal Bhupinder , Roberts Andrew W. , Rosenthal Mark A. , Shackleton Kylie , Silva Maria João , Siow Zhen R. , Smyth Gordon K. , Taylor Leanne , Travers Avraham , Yeo Belinda , Yeung Miriam M. , Bujak Andjelija Zivanovic , Dawson Sarah-Jane , Gray Daniel H.D. , Visvader Jane E. , Lindeman Geoffrey J.
Published: March 2024

Abstract
Venetoclax, a potent and selective BCL2 inhibitor, synergizes with endocrine therapy in preclinical models of ER-positive breast cancer. Using a phase Ib 3 + 3 dose-escalation and expansion study design, 33 patients with ER and BCL2-positive metastatic disease (mean prior regimens, 2; range, 0–8) were treated with daily tamoxifen (20 mg) and venetoclax (200–800 mg). Apart from uncomplicated “on-target” lymphopenia, no dose-limiting toxicities or high-grade adverse events were observed in the escalation phase (15 patients), and 800 mg was selected as the recommended phase II dose (RP2D). In the expansion phase (18 patients), few high-grade treatment-related adverse events were observed. For 24 patients treated at the RP2D, the confirmed radiologic response rate was 54% and the clinical benefit rate was 75%. Treatment responses were preempted by metabolic responses (FDG-PET) at 4 weeks and correlated with serial changes in circulating tumor DNA. Radiologic responses (40%) and clinical benefit (70%) were observed in 10 patients with plasma-detected ESR1 mutations.
Significance:
In the first clinical study to evaluate venetoclax in a solid tumor, we demonstrate that combining venetoclax with endocrine therapy has a tolerable safety profile and elicits notable activity in ER and BCL2-positive metastatic breast cancer. These findings support further investigation of combination therapy for patients with BCL2-positive tumors.

See related commentary by Drago et al., p. 323.

This article is highlighted in the In This Issue feature, p. 305
Data from A Stromal Lysolipid–Autotaxin Signaling Axis Promotes Pancreatic Tumor Progression
Authors: Auciello Francesca R. , Bulusu Vinay , Oon Chet , Tait-Mulder Jacqueline , Berry Mark , Bhattacharyya Sohinee , Tumanov Sergey , Allen-Petersen Brittany L. , Link Jason , Kendsersky Nicholas D. , Vringer Esmee , Schug Michelle , Novo David , Hwang Rosa F. , Evans Ronald M. , Nixon Colin , Dorrell Craig , Morton Jennifer P. , Norman Jim C. , Sears Rosalie C. , Kamphorst Jurre J. , Sherman Mara H.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) develops a pronounced stromal response reflecting an aberrant wound-healing process. This stromal reaction features transdifferentiation of tissue-resident pancreatic stellate cells (PSC) into activated cancer-associated fibroblasts, a process induced by PDAC cells but of unclear significance for PDAC progression. Here, we show that PSCs undergo a dramatic lipid metabolic shift during differentiation in the context of pancreatic tumorigenesis, including remodeling of the intracellular lipidome and secretion of abundant lipids in the activated, fibroblastic state. Specifically, stroma-derived lysophosphatidylcholines support PDAC cell synthesis of phosphatidylcholines, key components of cell membranes, and also facilitate production of the potent wound-healing mediator lysophosphatidic acid (LPA) by the extracellular enzyme autotaxin, which is overexpressed in PDAC. The autotaxin–LPA axis promotes PDAC cell proliferation, migration, and AKT activation, and genetic or pharmacologic autotaxin inhibition suppresses PDAC growth in vivo. Our work demonstrates how PDAC cells exploit the local production of wound-healing mediators to stimulate their own growth and migration.
Significance:
Our work highlights an unanticipated role for PSCs in producing the oncogenic LPA signaling lipid and demonstrates how PDAC tumor cells co-opt the release of wound-healing mediators by neighboring PSCs to promote their own proliferation and migration.

See related commentary by Biffi and Tuveson, p. 578.

This article is highlighted in the In This Issue feature, p. 565
Data from mTOR and HDAC Inhibitors Converge on the TXNIP/Thioredoxin Pathway to Cause Catastrophic Oxidative Stress and Regression of RAS-Driven Tumors
Authors: Malone Clare F. , Emerson Chloe , Ingraham Rachel , Barbosa William , Guerra Stephanie , Yoon Haejin , Liu Lin L. , Michor Franziska , Haigis Marcia , Macleod Kay F. , Maertens Ophélia , Cichowski Karen
Published: March 2024

Abstract
Although agents that inhibit specific oncogenic kinases have been successful in a subset of cancers, there are currently few treatment options for malignancies that lack a targetable oncogenic driver. Nevertheless, during tumor evolution cancers engage a variety of protective pathways, which may provide alternative actionable dependencies. Here, we identify a promising combination therapy that kills NF1-mutant tumors by triggering catastrophic oxidative stress. Specifically, we show that mTOR and HDAC inhibitors kill aggressive nervous system malignancies and shrink tumors in vivo by converging on the TXNIP/thioredoxin antioxidant pathway, through cooperative effects on chromatin and transcription. Accordingly, TXNIP triggers cell death by inhibiting thioredoxin and activating apoptosis signal-regulating kinase 1 (ASK1). Moreover, this drug combination also kills NF1-mutant and KRAS-mutant non–small cell lung cancers. Together, these studies identify a promising therapeutic combination for several currently untreatable malignancies and reveal a protective nodal point of convergence between these important epigenetic and oncogenic enzymes.

Significance: There are no effective therapies for NF1- or RAS-mutant cancers. We show that combined mTOR/HDAC inhibitors kill these RAS-driven tumors by causing catastrophic oxidative stress. This study identifies a promising therapeutic combination and demonstrates that selective enhancement of oxidative stress may be more broadly exploited for developing cancer therapies. Cancer Discov; 7(12); 1450–63. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1355
Data from Chimeric Antigen Receptor T Cell–Mediated Neurotoxicity in Nonhuman Primates
Authors: Taraseviciute Agne , Tkachev Victor , Ponce Rafael , Turtle Cameron J. , Snyder Jessica M. , Liggitt H. Denny , Myerson David , Gonzalez-Cuyar Luis , Baldessari Audrey , English Chris , Yu Alison , Zheng Hengqi , Furlan Scott N. , Hunt Daniel J. , Hoglund Virginia , Finney Olivia , Brakke Hannah , Blazar Bruce R. , Berger Carolina , Riddell Stanley R. , Gardner Rebecca , Kean Leslie S. , Jensen Michael C.
Published: March 2024

Abstract
Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell–mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/μL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell–mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan–T cell encephalitis.

Significance: We provide the first immunologically relevant, nonhuman primate model of B cell–directed CAR T-cell therapy–mediated CRS and neurotoxicity. We demonstrate CAR and non-CAR T-cell infiltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinflammatory cytokines in the CSF. Cancer Discov; 8(6); 750–63. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 663
Data from BCL6 Evolved to Enable Stress Tolerance in Vertebrates and Is Broadly Required by Cancer Cells to Adapt to Stress
Authors: Fernando Tharu M. , Marullo Rossella , Pera Gresely Benet , Phillip Jude M. , Yang Shao Ning , Lundell-Smith Geoffrey , Torregroza Ingrid , Ahn Haelee , Evans Todd , Győrffy Balázs , Privé Gilbert G. , Hirano Masayuki , Melnick Ari M. , Cerchietti Leandro
Published: March 2024

Abstract
Several lines of evidence link the canonical oncogene BCL6 to stress response. Here we demonstrate that BCL6 evolved in vertebrates as a component of the HSF1-driven stress response, which has been co-opted by the immune system to support germinal center formation and may have been decisive in the convergent evolution of humoral immunity in jawless and jawed vertebrates. We find that the highly conserved BTB corepressor binding site of BCL6 mediates stress adaptation across vertebrates. We demonstrate that pan-cancer cells hijack this stress tolerance mechanism to aberrantly express BCL6. Targeting the BCL6 BTB domain in cancer cells induces apoptosis and increases susceptibility to repeated doses of cytotoxic therapy. The chemosensitization effect upon BCL6 BTB inhibition is dependent on the derepression of TOX, implicating modulation of DNA repair as a downstream mechanism. Collectively, these data suggest a form of adaptive nononcogene addiction rooted in the natural selection of BCL6 during vertebrate evolution.
Significance:
We demonstrate that HSF1 drives BCL6 expression to enable stress tolerance in vertebrates. We identify an HSF1–BCL6–TOX stress axis that is required by cancer cells to tolerate exposure to cytotoxic agents and points toward BCL6-targeted therapy as a way to more effectively kill a wide variety of solid tumors.

This article is highlighted in the In This Issue feature, p. 565
Data from Cells Lacking the RB1 Tumor Suppressor Gene Are Hyperdependent on Aurora B Kinase for Survival
Authors: Oser Matthew G. , Fonseca Raquel , Chakraborty Abhishek A. , Brough Rachel , Spektor Alexander , Jennings Rebecca B. , Flaifel Abdallah , Novak Jesse S. , Gulati Aditi , Buss Elizabeth , Younger Scott T. , McBrayer Samuel K. , Cowley Glenn S. , Bonal Dennis M. , Nguyen Quang-De , Brulle-Soumare Laura , Taylor Paula , Cairo Stefano , Ryan Colm J. , Pease Elizabeth J. , Maratea Kim , Travers Jon , Root David E. , Signoretti Sabina , Pellman David , Ashton Susan , Lord Christopher J. , Barry Simon T. , Kaelin William G.
Published: March 2024

Abstract
Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating RB1 and TP53 mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical function of the RB1 gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an RB1−/− SCLC cell line that conditionally expresses RB1 to identify dependencies that are caused by RB1 loss and discovered that RB1−/− SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps other RB1−/− cancers.
Significance:
SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that RB1−/− SCLC are hyperdependent on AURKB, likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against RB1−/− SCLC tumors in mice at nontoxic doses.

See related commentary by Dick and Li, p. 169.

This article is highlighted in the In This Issue feature, p. 151
Data from Cellular Origin, Tumor Progression, and Pathogenic Mechanisms of Cutaneous Neurofibromas Revealed by Mice with Nf1 Knockout in Boundary Cap Cells
Authors: Radomska Katarzyna J. , Coulpier Fanny , Gresset Aurelie , Schmitt Alain , Debbiche Amal , Lemoine Sophie , Wolkenstein Pierre , Vallat Jean-Michel , Charnay Patrick , Topilko Piotr
Published: March 2024

Abstract
Patients carrying an inactive NF1 allele develop tumors of Schwann cell origin called neurofibromas (NF). Genetically engineered mouse models have significantly enriched our understanding of plexiform forms of NFs (pNF). However, this has not been the case for cutaneous neurofibromas (cNF), observed in all NF1 patients, as no previous model recapitulates their development. Here, we show that conditional Nf1 inactivation in Prss56-positive boundary cap cells leads to bona fide pNFs and cNFs. This work identifies subepidermal glia as a likely candidate for the cellular origin of cNFs and provides insights on disease mechanisms, revealing a long, multistep pathologic process in which inflammation-related signals play a pivotal role. This new mouse model is an important asset for future clinical and therapeutic investigations of NF1-associated neurofibromas.
Significance:
Patients affected by NF1 develop numerous cNFs. We present a mouse model that faithfully recapitulates cNFs, identify a candidate cell type at their origin, analyze the steps involved in their formation, and show that their development is dramatically accelerated by skin injury. These findings have important clinical/therapeutic implications.

This article is highlighted in the In This Issue feature, p. 1
Data from Exploiting MCL1 Dependency with Combination MEK + MCL1 Inhibitors Leads to Induction of Apoptosis and Tumor Regression in KRAS-Mutant Non–Small Cell Lung Cancer
Authors: Nangia Varuna , Siddiqui Faria M. , Caenepeel Sean , Timonina Daria , Bilton Samantha J. , Phan Nicole , Gomez-Caraballo Maria , Archibald Hannah L. , Li Chendi , Fraser Cameron , Rigas Diamanda , Vajda Kristof , Ferris Lorin A. , Lanuti Michael , Wright Cameron D. , Raskin Kevin A. , Cahill Daniel P. , Shin John H. , Keyes Colleen , Sequist Lecia V. , Piotrowska Zofia , Farago Anna F. , Azzoli Christopher G. , Gainor Justin F. , Sarosiek Kristopher A. , Brown Sean P. , Coxon Angela , Benes Cyril H. , Hughes Paul E. , Hata Aaron N.
Published: March 2024

Abstract
BH3 mimetic drugs, which inhibit prosurvival BCL2 family proteins, have limited single-agent activity in solid tumor models. The potential of BH3 mimetics for these cancers may depend on their ability to potentiate the apoptotic response to chemotherapy and targeted therapies. Using a novel class of potent and selective MCL1 inhibitors, we demonstrate that concurrent MEK + MCL1 inhibition induces apoptosis and tumor regression in KRAS-mutant non–small cell lung cancer (NSCLC) models, which respond poorly to MEK inhibition alone. Susceptibility to BH3 mimetics that target either MCL1 or BCL-xL was determined by the differential binding of proapoptotic BCL2 proteins to MCL1 or BCL-xL, respectively. The efficacy of dual MEK + MCL1 blockade was augmented by prior transient exposure to BCL-xL inhibitors, which promotes the binding of proapoptotic BCL2 proteins to MCL1. This suggests a novel strategy for integrating BH3 mimetics that target different BCL2 family proteins for KRAS-mutant NSCLC.
Significance:
Defining the molecular basis for MCL1 versus BCL-xL dependency will be essential for effective prioritization of BH3 mimetic combination therapies in the clinic. We discover a novel strategy for integrating BCL-xL and MCL1 inhibitors to drive and subsequently exploit apoptotic dependencies of KRAS-mutant NSCLCs treated with MEK inhibitors.

See related commentary by Leber et al., p. 1511.

This article is highlighted in the In This Issue feature, p. 1494
Data from Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities
Authors: Kelly Marcus R. , Kostyrko Kaja , Han Kyuho , Mooney Nancie A. , Jeng Edwin E. , Spees Kaitlyn , Dinh Phuong T. , Abbott Keene L. , Gwinn Dana M. , Sweet-Cordero E. Alejandro , Bassik Michael C. , Jackson Peter K.
Published: March 2024

Abstract
Activating mutations in RAS GTPases drive many cancers, but limited understanding of less-studied RAS interactors, and of the specific roles of different RAS interactor paralogs, continues to limit target discovery. We developed a multistage discovery and screening process to systematically identify genes conferring RAS-related susceptibilities in lung adenocarcinoma. Using affinity purification mass spectrometry, we generated a protein–protein interaction map of RAS interactors and pathway components containing hundreds of interactions. From this network, we constructed a CRISPR dual knockout library targeting 119 RAS-related genes that we screened for KRAS-dependent genetic interactions (GI). This approach identified new RAS effectors, including the adhesion controller RADIL and the endocytosis regulator RIN1, and >250 synthetic lethal GIs, including a potent KRAS-dependent interaction between RAP1GDS1 and RHOA. Many GIs link specific paralogs within and between gene families. These findings illustrate the power of multiomic approaches to uncover synthetic lethal combinations specific for hitherto untreatable cancer genotypes.
Significance:
We establish a deep network of protein–protein and genetic interactions in the RAS pathway. Many interactions validated here demonstrate important specificities and redundancies among paralogous RAS regulators and effectors. By comparing synthetic lethal interactions across KRAS-dependent and KRAS-independent cell lines, we identify several new combination therapy targets for RAS-driven cancers.

This article is highlighted in the In This Issue feature, p. 1775
Data from Pan-Cancer Efficacy of Vemurafenib in BRAFV600-Mutant Non-Melanoma Cancers
Authors: Subbiah Vivek , Puzanov Igor , Blay Jean-Yves , Chau Ian , Lockhart A. Craig , Raje Noopur S. , Wolf Juergen , Baselga José , Meric-Bernstam Funda , Roszik Jason , Diamond Eli L. , Riely Gregory J. , Sherman Eric J. , Riehl Todd , Pitcher Bethany , Hyman David M.
Published: March 2024

Abstract
BRAFV600 mutations occur in a wide range of tumor types, and RAF inhibition has become standard in several of these cancers. Despite this progress, BRAFV600 mutations have historically been considered a clear demonstration of tumor lineage context–dependent oncogene addiction, based predominantly on the insensitivity to RAF inhibition in colorectal cancer. However, the true broader activity of RAF inhibition pan-cancer remains incompletely understood. To address this, we conducted a multicohort “basket” study of the BRAF inhibitor vemurafenib in non-melanoma BRAFV600 mutation–positive solid tumors. In total, 172 patients with 26 unique cancer types were treated, achieving an overall response rate of 33% and median duration of response of 13 months. Responses were observed in 13 unique cancer types, including historically treatment-refractory tumor types such as cholangiocarcinoma, sarcoma, glioma, neuroendocrine carcinoma, and salivary gland carcinomas. Collectively, these data demonstrate that single-agent BRAF inhibition has broader clinical activity than previously recognized.
Significance:
These data suggest that BRAFV600 mutations lead to oncogene addiction and are clinically actionable in a broad range of non-melanoma cancers, including tumor types in which RAF inhibition is not currently considered standard of care.

See related commentary by Ribas and Lo, p. 640.

This article is highlighted in the In This Issue feature, p. 627