bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Canonical Wnt/β-catenin Signaling Drives Human Schwann Cell Transformation, Progression, and Tumor Maintenance
Authors: Watson Adrienne L. , Rahrmann Eric P. , Moriarity Branden S. , Choi Kwangmin , Conboy Caitlin B. , Greeley Andrew D. , Halfond Amanda L. , Anderson Leah K. , Wahl Brian R. , Keng Vincent W. , Rizzardi Anthony E. , Forster Colleen L. , Collins Margaret H. , Sarver Aaron L. , Wallace Margaret R. , Schmechel Stephen C. , Ratner Nancy , Largaespada David A.
Published: March 2024

Abstract
Genetic changes required for the formation and progression of human Schwann cell tumors remain elusive. Using a Sleeping Beauty forward genetic screen, we identified several genes involved in canonical Wnt signaling as potential drivers of benign neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). In human neurofibromas and MPNSTs, activation of Wnt signaling increased with tumor grade and was associated with downregulation of β-catenin destruction complex members or overexpression of a ligand that potentiates Wnt signaling, R-spondin 2 (RSPO2). Induction of Wnt signaling was sufficient to induce transformed properties in immortalized human Schwann cells, and downregulation of this pathway was sufficient to reduce the tumorigenic phenotype of human MPNST cell lines. Small-molecule inhibition of Wnt signaling effectively reduced the viability of MPNST cell lines and synergistically induced apoptosis when combined with an mTOR inhibitor, RAD-001, suggesting that Wnt inhibition represents a novel target for therapeutic intervention in Schwann cell tumors.

Significance: We show canonical Wnt/β-catenin signaling is a novel genetic driver of Schwann cell tumor development and progression, due to downregulation of β-catenin destruction complex members and overexpression of RSPO2. Inhibitors of Wnt signaling alone, or in combination with RAD-001, may have therapeutic value for patients with MPNSTs or neurofibromas. Cancer Discov; 3(6); 674–89. ©2013 AACR.

See related commentary by Reilly, p. 610

This article is highlighted in the In This Issue feature, p. 591
Data from EGFR Kinase Domain Duplication (EGFR-KDD) Is a Novel Oncogenic Driver in Lung Cancer That Is Clinically Responsive to Afatinib
Authors: Gallant Jean-Nicolas , Sheehan Jonathan H. , Shaver Timothy M. , Bailey Mark , Lipson Doron , Chandramohan Raghu , Brewer Monica Red , York Sally J. , Kris Mark G. , Pietenpol Jennifer A. , Ladanyi Marc , Miller Vincent A. , Ali Siraj M. , Meiler Jens , Lovly Christine M.
Published: March 2024

Abstract
Oncogenic EGFR mutations are found in 10% to 35% of lung adenocarcinomas. Such mutations, which present most commonly as small in-frame deletions in exon 19 or point mutations in exon 21 (L858R), confer sensitivity to EGFR tyrosine kinase inhibitors (TKI). In analyzing the tumor from a 33-year-old male never-smoker, we identified a novel EGFR alteration in lung cancer: EGFR exon 18–25 kinase domain duplication (EGFR-KDD). Through analysis of a larger cohort of tumor samples, we detected additional cases of EGFR-KDD in lung, brain, and other cancers. In vitro, EGFR-KDD is constitutively active, and computational modeling provides potential mechanistic support for its auto-activation. EGFR-KDD–transformed cells are sensitive to EGFR TKIs and, consistent with these in vitro findings, the index patient had a partial response to the EGFR TKI afatinib. The patient eventually progressed, at which time resequencing revealed an EGFR-dependent mechanism of acquired resistance to afatinib, thereby validating EGFR-KDD as a driver alteration and therapeutic target.

Significance: We identified oncogenic and drug-sensitive EGFR-KDD that is recurrent in lung, brain, and soft-tissue cancers and documented that a patient with metastatic lung adenocarcinoma harboring the EGFR-KDD derived significant antitumor response from treatment with the EGFR inhibitor afatinib. Findings from these studies will be immediately translatable, as there are already several approved EGFR inhibitors in clinical use. Cancer Discov; 5(11); 1155–63. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1111
Data from Harnessing Connectivity in a Large-Scale Small-Molecule Sensitivity Dataset
Authors: Seashore-Ludlow Brinton , Rees Matthew G. , Cheah Jaime H. , Cokol Murat , Price Edmund V. , Coletti Matthew E. , Jones Victor , Bodycombe Nicole E. , Soule Christian K. , Gould Joshua , Alexander Benjamin , Li Ava , Montgomery Philip , Wawer Mathias J. , Kuru Nurdan , Kotz Joanne D. , Hon C. Suk-Yee , Munoz Benito , Liefeld Ted , Dančík Vlado , Bittker Joshua A. , Palmer Michelle , Bradner James E. , Shamji Alykhan F. , Clemons Paul A. , Schreiber Stuart L.
Published: March 2024

Abstract
Identifying genetic alterations that prime a cancer cell to respond to a particular therapeutic agent can facilitate the development of precision cancer medicines. Cancer cell-line (CCL) profiling of small-molecule sensitivity has emerged as an unbiased method to assess the relationships between genetic or cellular features of CCLs and small-molecule response. Here, we developed annotated cluster multidimensional enrichment analysis to explore the associations between groups of small molecules and groups of CCLs in a new, quantitative sensitivity dataset. This analysis reveals insights into small-molecule mechanisms of action, and genomic features that associate with CCL response to small-molecule treatment. We are able to recapitulate known relationships between FDA-approved therapies and cancer dependencies and to uncover new relationships, including for KRAS-mutant cancers and neuroblastoma. To enable the cancer community to explore these data, and to generate novel hypotheses, we created an updated version of the Cancer Therapeutic Response Portal (CTRP v2).

Significance: We present the largest CCL sensitivity dataset yet available, and an analysis method integrating information from multiple CCLs and multiple small molecules to identify CCL response predictors robustly. We updated the CTRP to enable the cancer research community to leverage these data and analyses. Cancer Discov; 5(11); 1210–23. ©2015 AACR.

See related commentary by Gray and Mills, p. 1130.

This article is highlighted in the In This Issue feature, p. 1111
Data from Targeting the BRAF V600E Mutation in Multiple Myeloma
Authors: Andrulis Mindaugas , Lehners Nicola , Capper David , Penzel Roland , Heining Christoph , Huellein Jennifer , Zenz Thorsten , von Deimling Andreas , Schirmacher Peter , Ho Anthony D. , Goldschmidt Hartmut , Neben Kai , Raab Marc S.
Published: March 2024

Abstract
In multiple myeloma, there has been little progress in the specific therapeutic targeting of oncogenic mutations. Whole-genome sequencing data have recently revealed that a subset of patients carry an activating mutation (V600E) in the BRAF kinase. To uncover the clinical relevance of this mutation in multiple myeloma, we correlated the mutation status in primary tumor samples from 379 patients with myeloma with disease outcome. We found a significantly higher incidence of extramedullary disease and a shorter overall survival in mutation carriers when compared with controls. Most importantly, we report on a patient with confirmed BRAF V600E mutation and relapsed myeloma with extensive extramedullary disease, refractory to all approved therapeutic options, who has rapidly and durably responded to low doses of the mutation-specific BRAF inhibitor vermurafenib. Collectively, we provide evidence for the development of the BRAF V600E mutation in the context of clonal evolution and describe the prognostic and therapeutic relevance of this targetable mutation.

Significance: This is the first evidence of the clinical and therapeutic relevance of BRAF V600E mutations in multiple myeloma, proving the principle of specific inhibition of driver mutations in this disease. Cancer Discov; 3(8); 862–9. ©2013 AACR.

See related commentary by O'Donnell and Raje, p. 840

This article is highlighted in the In This Issue feature, p. 826
Data from The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma
Authors: Van Allen Eliezer M. , Wagle Nikhil , Sucker Antje , Treacy Daniel J. , Johannessen Cory M. , Goetz Eva M. , Place Chelsea S. , Taylor-Weiner Amaro , Whittaker Steven , Kryukov Gregory V. , Hodis Eran , Rosenberg Mara , McKenna Aaron , Cibulskis Kristian , Farlow Deborah , Zimmer Lisa , Hillen Uwe , Gutzmer Ralf , Goldinger Simone M. , Ugurel Selma , Gogas Helen J. , Egberts Friederike , Berking Carola , Trefzer Uwe , Loquai Carmen , Weide Benjamin , Hassel Jessica C. , Gabriel Stacey B. , Carter Scott L. , Getz Gad , Garraway Levi A. , Schadendorf Dirk
Published: March 2024

Abstract
Most patients with BRAFV600-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAFV600-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a “long tail” of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAFV600-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.

Significance: The use of RAF inhibitors for BRAFV600-mutant metastatic melanoma improves patient outcomes, but most patients demonstrate early or acquired resistance to this targeted therapy. We reveal the genetic landscape of clinical resistance mechanisms to RAF inhibitors from patients using whole-exome sequencing, and experimentally assess new observed mechanisms to define potential subsequent treatment strategies. Cancer Discov; 4(1); 94–109. ©2013 AACR.

See related commentary by Solit and Rosen, p. 27

This article is highlighted in the In This Issue feature, p. 1
Data from The Master Neural Transcription Factor BRN2 Is an Androgen Receptor–Suppressed Driver of Neuroendocrine Differentiation in Prostate Cancer
Authors: Bishop Jennifer L. , Thaper Daksh , Vahid Sepideh , Davies Alastair , Ketola Kirsi , Kuruma Hidetoshi , Jama Randy , Nip Ka Mun , Angeles Arkhjamil , Johnson Fraser , Wyatt Alexander W. , Fazli Ladan , Gleave Martin E. , Lin Dong , Rubin Mark A. , Collins Colin C. , Wang Yuzhuo , Beltran Himisha , Zoubeidi Amina
Published: March 2024

Abstract
Mechanisms controlling the emergence of lethal neuroendocrine prostate cancer (NEPC), especially those that are consequences of treatment-induced suppression of the androgen receptor (AR), remain elusive. Using a unique model of AR pathway inhibitor–resistant prostate cancer, we identified AR-dependent control of the neural transcription factor BRN2 (encoded by POU3F2) as a major driver of NEPC and aggressive tumor growth, both in vitro and in vivo. Mechanistic studies showed that AR directly suppresses BRN2 transcription, which is required for NEPC, and BRN2-dependent regulation of the NEPC marker SOX2. Underscoring its inverse correlation with classic AR activity in clinical samples, BRN2 expression was highest in NEPC tumors and was significantly increased in castration-resistant prostate cancer compared with adenocarcinoma, especially in patients with low serum PSA. These data reveal a novel mechanism of AR-dependent control of NEPC and suggest that targeting BRN2 is a strategy to treat or prevent neuroendocrine differentiation in prostate tumors.

Significance: Understanding the contribution of the AR to the emergence of highly lethal, drug-resistant NEPC is critical for better implementation of current standard-of-care therapies and novel drug design. Our first-in-field data underscore the consequences of potent AR inhibition in prostate tumors, revealing a novel mechanism of AR-dependent control of neuroendocrine differentiation, and uncover BRN2 as a potential therapeutic target to prevent emergence of NEPC. Cancer Discov; 7(1); 54–71. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 1
Data from Epigenetic Reprogramming Sensitizes CML Stem Cells to Combined EZH2 and Tyrosine Kinase Inhibition
Authors: Scott Mary T. , Korfi Koorosh , Saffrey Peter , Hopcroft Lisa E.M. , Kinstrie Ross , Pellicano Francesca , Guenther Carla , Gallipoli Paolo , Cruz Michelle , Dunn Karen , Jorgensen Heather G. , Cassels Jennifer E. , Hamilton Ashley , Crossan Andrew , Sinclair Amy , Holyoake Tessa L. , Vetrie David
Published: March 2024

Abstract
A major obstacle to curing chronic myeloid leukemia (CML) is residual disease maintained by tyrosine kinase inhibitor (TKI)–persistent leukemic stem cells (LSC). These are BCR–ABL1 kinase independent, refractory to apoptosis, and serve as a reservoir to drive relapse or TKI resistance. We demonstrate that Polycomb Repressive Complex 2 is misregulated in chronic phase CML LSCs. This is associated with extensive reprogramming of H3K27me3 targets in LSCs, thus sensitizing them to apoptosis upon treatment with an EZH2-specific inhibitor (EZH2i). EZH2i does not impair normal hematopoietic stem cell survival. Strikingly, treatment of primary CML cells with either EZH2i or TKI alone caused significant upregulation of H3K27me3 targets, and combined treatment further potentiated these effects and resulted in significant loss of LSCs compared to TKI alone, in vitro, and in long-term bone marrow murine xenografts. Our findings point to a promising epigenetic-based therapeutic strategy to more effectively target LSCs in patients with CML receiving TKIs.

Significance: In CML, TKI-persistent LSCs remain an obstacle to cure, and approaches to eradicate them remain a significant unmet clinical need. We demonstrate that EZH2 and H3K27me3 reprogramming is important for LSC survival, but renders LSCs sensitive to the combined effects of EZH2i and TKI. This represents a novel approach to more effectively target LSCs in patients receiving TKI treatment. Cancer Discov; 6(11); 1248–57. ©2016 AACR.

See related article by Xie et al., p. 1237.

This article is highlighted in the In This Issue feature, p. 1197
Data from Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer
Authors: Le Xiuning , Antony Rajee , Razavi Pedram , Treacy Daniel J. , Luo Flora , Ghandi Mahmoud , Castel Pau , Scaltriti Maurizio , Baselga José , Garraway Levi A.
Published: March 2024

Abstract
PIK3CA (which encodes the PI3K alpha isoform) is the most frequently mutated oncogene in breast cancer. Small-molecule PI3K inhibitors have shown promise in clinical trials; however, intrinsic and acquired resistance limits their utility. We used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Among the validated resistance genes, Proviral Insertion site in Murine leukemia virus (PIM) kinases conferred resistance by maintaining downstream PI3K effector activation in an AKT-independent manner. Concurrent pharmacologic inhibition of PIM and PI3K overcame this resistance mechanism. We also observed increased PIM expression and activity in a subset of breast cancer biopsies with clinical resistance to PI3K inhibitors. PIM1 overexpression was mutually exclusive with PIK3CA mutation in treatment-naïve breast cancers, suggesting downstream functional redundancy. Together, these results offer new insights into resistance to PI3K inhibitors and support clinical studies of combined PIM/PI3K inhibition in a subset of PIK3CA-mutant cancers.

Significance: PIM kinase overexpression confers resistance to small-molecule PI3K inhibitors. Combined inhibition of PIM and PI3K may therefore be warranted in a subset of breast cancers. Cancer Discov; 6(10); 1134–47. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 1069
Data from Long-Range Chromatin Interactions Drive Mutant TERT Promoter Activation
Authors: Akıncılar Semih Can , Khattar Ekta , Boon Priscilla Li Shan , Unal Bilal , Fullwood Melissa Jane , Tergaonkar Vinay
Published: March 2024

Abstract
Cancer-specific TERT promoter mutations (-146C>T and -124C>T) have been linked to reactivation of the epigenetically silenced telomerase reverse transcriptase gene (TERT). Understanding how these single-nucleotide alterations drive TERT reactivation is a fundamental unanswered question and is key for making successful therapeutics. We show that unlike wild-type promoters, recruitment of the transcription factor GABPA specifically to mutant TERT promoters mediates long-range chromatin interaction and enrichment of active histone marks, and hence drives TERT transcription. CRISPR-mediated reversal of mutant TERT promoters, or deletion of its long-range interacting chromatin, abrogates GABPA binding and long-range interactions, leading to depletion of active histone marks, loss of POL2 recruitment, and suppression of TERT transcription. In contrast, de novo introduction of a TERT promoter mutation enables GABPA binding and upregulation of TERT via long-range interactions, acquisition of active histone marks, and subsequent POL2 recruitment. This study provides a unifying mechanistic insight into activation of mutant TERT promoters across various human cancers.

Significance: This study identifies a key mechanism by which cancer-specific mutant TERT promoters cause reactivation of TERT. Because the mechanism uncovered here is not utilized by promoters that drive TERT in normal cells, this mechanism could be exploited to make inhibitors which have the potential to block telomerase function and hence the progression of up to 90% of human cancers. Cancer Discov; 6(11); 1276–91. ©2016 AACR.

See related commentary by Min and Shay, p. 1212.

This article is highlighted in the In This Issue feature, p. 1197
Data from Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline BRCA1/2 Mutations and Selected Sporadic Cancers
Authors: de Bono Johann , Ramanathan Ramesh K. , Mina Lida , Chugh Rashmi , Glaspy John , Rafii Saeed , Kaye Stan , Sachdev Jasgit , Heymach John , Smith David C. , Henshaw Joshua W. , Herriott Ashleigh , Patterson Miranda , Curtin Nicola J. , Byers Lauren Averett , Wainberg Zev A.
Published: March 2024

Abstract
Talazoparib inhibits PARP catalytic activity, trapping PARP1 on damaged DNA and causing cell death in BRCA1/2-mutated cells. We evaluated talazoparib therapy in this two-part, phase I, first-in-human trial. Antitumor activity, MTD, pharmacokinetics, and pharmacodynamics of once-daily talazoparib were determined in an open-label, multicenter, dose-escalation study (NCT01286987). The MTD was 1.0 mg/day, with an elimination half-life of 50 hours. Treatment-related adverse events included fatigue (26/71 patients; 37%) and anemia (25/71 patients; 35%). Grade 3 to 4 adverse events included anemia (17/71 patients; 24%) and thrombocytopenia (13/71 patients; 18%). Sustained PARP inhibition was observed at doses ≥0.60 mg/day. At 1.0 mg/day, confirmed responses were observed in 7 of 14 (50%) and 5 of 12 (42%) patients with BRCA mutation–associated breast and ovarian cancers, respectively, and in patients with pancreatic and small cell lung cancer. Talazoparib demonstrated single-agent antitumor activity and was well tolerated in patients at the recommended dose of 1.0 mg/day.

Significance: In this clinical trial, we show that talazoparib has single-agent antitumor activity and a tolerable safety profile. At its recommended phase II dose of 1.0 mg/day, confirmed responses were observed in patients with BRCA mutation–associated breast and ovarian cancers and in patients with pancreatic and small cell lung cancer. Cancer Discov; 7(6); 620–9. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 539
Data from Epithelial-to-Mesenchymal Transition Defines Feedback Activation of Receptor Tyrosine Kinase Signaling Induced by MEK Inhibition in KRAS-Mutant Lung Cancer
Authors: Kitai Hidenori , Ebi Hiromichi , Tomida Shuta , Floros Konstantinos V. , Kotani Hiroshi , Adachi Yuta , Oizumi Satoshi , Nishimura Masaharu , Faber Anthony C. , Yano Seiji
Published: March 2024

Abstract
KRAS is frequently mutated in lung cancer. Whereas MAPK is a well-known effector pathway of KRAS, blocking this pathway with clinically available MAPK inhibitors is relatively ineffective. Here, we report that epithelial-to-mesenchymal transition rewires the expression of receptor tyrosine kinases, leading to differential feedback activation of the MAPK pathway following MEK inhibition. In epithelial-like KRAS-mutant lung cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like KRAS-mutant lung cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor (MEKi) and an FGFR inhibitor (FGFRi) induced cell death in vitro and tumor regressions in vivo. These data establish the rationale and a therapeutic approach to treat mesenchymal-like KRAS-mutant lung cancers effectively with clinically available FGFR1 and MAPK inhibitors.

Significance: Adaptive resistance to MEKi is driven by receptor tyrosine kinases specific to the differentiation state of the KRAS-mutant non–small cell lung cancer (NSCLC). In mesenchymal-like KRAS-mutant NSCLC, FGFR1 is highly expressed, and MEK inhibition relieves feedback suppression of FGFR1, resulting in reactivation of ERK; suppression of ERK by MEKi/FGFRi combination results in tumor shrinkage. Cancer Discov; 6(7); 754–69. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 681
Data from Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer
Authors: Russo Mariangela , Siravegna Giulia , Blaszkowsky Lawrence S. , Corti Giorgio , Crisafulli Giovanni , Ahronian Leanne G. , Mussolin Benedetta , Kwak Eunice L. , Buscarino Michela , Lazzari Luca , Valtorta Emanuele , Truini Mauro , Jessop Nicholas A. , Robinson Hayley E. , Hong Theodore S. , Mino-Kenudson Mari , Di Nicolantonio Federica , Thabet Ashraf , Sartore-Bianchi Andrea , Siena Salvatore , Iafrate A. John , Bardelli Alberto , Corcoran Ryan B.
Published: March 2024

Abstract
How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown. We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses. Biopsy of a patient's progressing liver metastasis following prolonged response to cetuximab revealed a MEK1K57T mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In circulating tumor DNA (ctDNA), mutant MEK1 levels declined with treatment, but a previously unrecognized KRASQ61H mutation was also identified that increased despite therapy. This same KRAS mutation was later found in a separate nonresponding metastasis. In summary, parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion-specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient.

Significance: Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance. Cancer Discov; 6(2); 147–53. ©2015 AACR.

See related commentary by Hiley and Swanton, p. 122.

This article is highlighted in the In This Issue feature, p. 109
Data from Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers
Authors: Watkins Johnathan , Weekes Daniel , Shah Vandna , Gazinska Patrycja , Joshi Shalaka , Sidhu Bhavna , Gillett Cheryl , Pinder Sarah , Vanoli Fabio , Jasin Maria , Mayrhofer Markus , Isaksson Anders , Cheang Maggie C.U. , Mirza Hasan , Frankum Jessica , Lord Christopher J. , Ashworth Alan , Vinayak Shaveta , Ford James M. , Telli Melinda L. , Grigoriadis Anita , Tutt Andrew N.J.
Published: March 2024

Abstract
Triple-negative breast cancers (TNBC) are characterized by a wide spectrum of genomic alterations, some of which might be caused by defects in DNA repair processes such as homologous recombination (HR). Despite this understanding, associating particular patterns of genomic instability with response to therapy has been challenging. Here, we show that allelic-imbalanced copy-number aberrations (AiCNA) are more prevalent in TNBCs that respond to platinum-based chemotherapy, thus providing a candidate predictive biomarker for this disease. Furthermore, we show that a high level of AiCNA is linked with elevated expression of a meiosis-associated gene, HORMAD1. Elevated HORMAD1 expression suppresses RAD51-dependent HR and drives the use of alternative forms of DNA repair, the generation of AiCNAs, as well as sensitizing cancer cells to HR-targeting therapies. Our data therefore provide a mechanistic association between HORMAD1 expression, a specific pattern of genomic instability, and an association with response to platinum-based chemotherapy in TNBC.

Significance: Previous studies have shown correlation between mutational “scars” and sensitivity to platinums extending beyond associations with BRCA1/2 mutation, but do not elucidate the mechanism. Here, a novel allele-specific copy-number characterization of genome instability identifies and functionally validates the inappropriate expression of the meiotic gene HORMAD1 as a driver of HR deficiency in TNBC, acting to induce allelic imbalance and moderate platinum and PARP inhibitor sensitivity with implications for the use of such “scars” and expression of meiotic genes as predictive biomarkers. Cancer Discov; 5(5); 488–505. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 453
Data from Phase IB Study of Vemurafenib in Combination with Irinotecan and Cetuximab in Patients with Metastatic Colorectal Cancer with BRAFV600E Mutation
Authors: Hong David S. , Morris Van K. , El Osta Badi , Sorokin Alexey V. , Janku Filip , Fu Siqing , Overman Michael J. , Piha-Paul Sarina , Subbiah Vivek , Kee Bryan , Tsimberidou Apostolia M. , Fogelman David , Bellido Jorge , Shureiqi Imad , Huang Helen , Atkins Johnique , Tarcic Gabi , Sommer Nicolas , Lanman Richard , Meric-Bernstam Funda , Kopetz Scott
Published: March 2024

Abstract
In vitro, EGFR inhibition, combined with the BRAF inhibitor vemurafenib, causes synergistic cytotoxicity for BRAFV600E metastatic colorectal cancer, further augmented by irinotecan. The safety and efficacy of vemurafenib, irinotecan, and cetuximab in BRAF-mutated malignancies are not defined. In this 3+3 phase I study, patients with BRAFV600E-advanced solid cancers received cetuximab and irinotecan with escalating doses of vemurafenib. Nineteen patients (18 with metastatic colorectal cancer and 1 with appendiceal cancer) were enrolled. Three patients experienced dose-limiting toxicities. The MTD of vemurafenib was 960 mg twice daily. Six of 17 evaluable patients (35%) achieved a radiographic response by Response Evaluation Criteria in Solid Tumors 1.1 criteria, consistent with in vivo models demonstrating tumor regressions with the triplet regimen. Median progression-free survival was 7.7 months. BRAFV600E circulating cell-free DNA (cfDNA) trends correlated with radiographic changes, and acquired mutations from cfDNA in genes reactivating MAPK signaling were observed at progression.

Significance: Vemurafenib, in combination with irinotecan and cetuximab, was well tolerated in patients with refractory, BRAF-mutated metastatic colorectal cancer, and both survival outcomes and response rates exceeded prior reports for vemurafenib and for irinotecan plus cetuximab in BRAFV600E metastatic colorectal cancer. In vivo models demonstrated regressions with the triplet, in contrast with vemurafenib and cetuximab alone. cfDNA predicted radiographic response and identified mutations reactivating the MAPK pathway upon progression. Cancer Discov; 6(12); 1352–65. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 1293
Data from EGFR Fusions as Novel Therapeutic Targets in Lung Cancer
Authors: Konduri Kartik , Gallant Jean-Nicolas , Chae Young Kwang , Giles Francis J. , Gitlitz Barbara J. , Gowen Kyle , Ichihara Eiki , Owonikoko Taofeek K. , Peddareddigari Vijay , Ramalingam Suresh S. , Reddy Satyanarayan K. , Eaby-Sandy Beth , Vavalà Tiziana , Whiteley Andrew , Chen Heidi , Yan Yingjun , Sheehan Jonathan H. , Meiler Jens , Morosini Deborah , Ross Jeffrey S. , Stephens Philip J. , Miller Vincent A. , Ali Siraj M. , Lovly Christine M.
Published: March 2024

Abstract
Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR–RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration.

Significance: We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors. Cancer Discov; 6(6); 601–11. ©2016 AACR.

See related commentary by Paik, p. 574.

This article is highlighted in the In This Issue feature, p. 561
Data from Synthetic Lethal Approaches Exploiting DNA Damage in Aggressive Myeloma
Authors: Cottini Francesca , Hideshima Teru , Suzuki Rikio , Tai Yu-Tzu , Bianchini Giampaolo , Richardson Paul G. , Anderson Kenneth C. , Tonon Giovanni
Published: March 2024

Abstract
Ongoing DNA damage is a common feature of epithelial cancers. Here, we show that tumor cells derived from multiple myeloma, a disease of clonal plasma cells, demonstrate DNA-replicative stress, leading to DNA damage. We identified a poor-prognosis subset of multiple myeloma with extensive chromosomal instability and replicative stress, which rely on ATR to compensate for DNA-replicative stress; conversely, silencing of ATR or treatment with a specific ATR inhibitor triggers multiple myeloma cell apoptosis. We show that oncogenes, such as MYC, induce DNA damage in multiple myeloma cells not only by increased replicative stress, but also via increased oxidative stress, and that reactive oxygen species–inducer piperlongumine triggers further DNA damage and apoptosis. Importantly, ATR inhibition combined with piperlongumine triggers synergistic multiple myeloma cytotoxicity. This synthetic lethal approach, enhancing oxidative stress while concomitantly blocking replicative stress response, provides a novel combination targeted therapy to address an unmet medical need in this subset of multiple myeloma.

Significance: Multiple myeloma remains an incurable disease. We have identified a subset of multiple myeloma patients with poor prognosis, whose tumors present chromosomal instability, replicative and oxidative stress, and DNA damage. We define a synthetic lethal approach enhancing oxidative stress while targeting replicative stress response, inducing tumor cell apoptosis in this patient subset. Cancer Discov; 5(9); 972–87. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 893
Data from Recurrent Fusions in MYB and MYBL1 Define a Common, Transcription Factor–Driven Oncogenic Pathway in Salivary Gland Adenoid Cystic Carcinoma
Authors: Brayer Kathryn J. , Frerich Candace A. , Kang Huining , Ness Scott A.
Published: March 2024

Abstract
Adenoid cystic carcinoma (ACC), the second most common malignancy of salivary glands, is a rare tumor with a bleak prognosis for which therapeutic targets are unavailable. We used RNA sequencing (RNA-seq) to analyze low-quality RNA from archival, formaldehyde-fixed, paraffin-embedded samples. In addition to detecting the most common ACC translocation, t(6;9) fusing the MYB proto-oncogene to NFIB, we also detected previously unknown t(8;9) and t(8;14) translocations fusing the MYBL1 gene to the NFIB and RAD51B genes, respectively. RNA-seq provided information about gene fusions, alternative RNA splicing, and gene expression signatures. Interestingly, tumors with MYB and MYBL1 translocations displayed similar gene expression profiles, and the combined MYB and MYBL1 expression correlated with outcome, suggesting that the related MYB proteins are interchangeable oncogenic drivers in ACC. Our results provide important details about the biology of ACC and illustrate how archival tissue samples can be used for detailed molecular analyses of rare tumors.

Significance: Using RNA-seq to perform whole-transcriptome analysis of archival ACC tumor samples, we identified novel, recurrent gene fusions, detected alternative RNA splicing, and established gene expression signatures that provide detailed information about the biology of ACC tumors. Cancer Discov; 6(2); 176–87. ©2015 AACR.

See related commentary by Gonda and Ramsay, p. 125.

This article is highlighted in the In This Issue feature, p. 109
Data from Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120
Authors: Chen Shih-Hsun , Zhang Youyan , Van Horn Robert D. , Yin Tinggui , Buchanan Sean , Yadav Vipin , Mochalkin Igor , Wong Swee Seong , Yue Yong Gang , Huber Lysiane , Conti Ilaria , Henry James R. , Starling James J. , Plowman Gregory D. , Peng Sheng-Bin
Published: March 2024

Abstract
We have identified previously undiscovered BRAF in-frame deletions near the αC-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the β3/αC-helix loop and hinder its flexibility by locking the helix in the active αC-helix-in conformation that favors dimer formation. Expression of L485-P490–deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer–dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive.

Significance: This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer. Cancer Discov; 6(3); 300–15. ©2016 AACR.

This article is highlighted in the In This Issue feature, p. 217
Data from Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non–Small Cell Lung Cancer, and Other Solid Tumors
Authors: Patnaik Amita , Rosen Lee S. , Tolaney Sara M. , Tolcher Anthony W. , Goldman Jonathan W. , Gandhi Leena , Papadopoulos Kyriakos P. , Beeram Muralidhar , Rasco Drew W. , Hilton John F. , Nasir Aejaz , Beckmann Richard P. , Schade Andrew E. , Fulford Angie D. , Nguyen Tuan S. , Martinez Ricardo , Kulanthaivel Palaniappan , Li Lily Q. , Frenzel Martin , Cronier Damien M. , Chan Edward M. , Flaherty Keith T. , Wen Patrick Y. , Shapiro Geoffrey I.
Published: March 2024

Abstract
We evaluated the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of abemaciclib, an orally bioavailable inhibitor of cyclin-dependent kinases (CDK) 4 and 6, in a multicenter study including phase I dose escalation followed by tumor-specific cohorts for breast cancer, non–small cell lung cancer (NSCLC), glioblastoma, melanoma, and colorectal cancer. A total of 225 patients were enrolled: 33 in dose escalation and 192 in tumor-specific cohorts. Dose-limiting toxicity was grade 3 fatigue. The maximum tolerated dose was 200 mg every 12 hours. The most common possibly related treatment-emergent adverse events involved fatigue and the gastrointestinal, renal, or hematopoietic systems. Plasma concentrations increased with dose, and pharmacodynamic effects were observed in proliferating keratinocytes and tumors. Radiographic responses were achieved in previously treated patients with breast cancer, NSCLC, and melanoma. For hormone receptor–positive breast cancer, the overall response rate was 31%; moreover, 61% of patients achieved either response or stable disease lasting ≥6 months.

Significance: Abemaciclib represents the first selective inhibitor of CDK4 and CDK6 with a safety profile allowing continuous dosing to achieve sustained target inhibition. This first-in-human experience demonstrates single-agent activity for patients with advanced breast cancer, NSCLC, and other solid tumors. Cancer Discov; 6(7); 740–53. ©2016 AACR.

See related commentary by Lim et al., p. 697.

This article is highlighted in the In This Issue feature, p. 681
Data from A Genome-Wide Scan Identifies Variants in NFIB Associated with Metastasis in Patients with Osteosarcoma
Authors: Mirabello Lisa , Koster Roelof , Moriarity Branden S. , Spector Logan G. , Meltzer Paul S. , Gary Joy , Machiela Mitchell J. , Pankratz Nathan , Panagiotou Orestis A. , Largaespada David , Wang Zhaoming , Gastier-Foster Julie M. , Gorlick Richard , Khanna Chand , de Toledo Silvia Regina Caminada , Petrilli Antonio S. , Patiño-Garcia Ana , Sierrasesúmaga Luis , Lecanda Fernando , Andrulis Irene L. , Wunder Jay S. , Gokgoz Nalan , Serra Massimo , Hattinger Claudia , Picci Piero , Scotlandi Katia , Flanagan Adrienne M. , Tirabosco Roberto , Amary Maria Fernanda , Halai Dina , Ballinger Mandy L. , Thomas David M. , Davis Sean , Barkauskas Donald A. , Marina Neyssa , Helman Lee , Otto George M. , Becklin Kelsie L. , Wolf Natalie K. , Weg Madison T. , Tucker Margaret , Wacholder Sholom , Fraumeni Joseph F. , Caporaso Neil E. , Boland Joseph F. , Hicks Belynda D. , Vogt Aurelie , Burdett Laurie , Yeager Meredith , Hoover Robert N. , Chanock Stephen J. , Savage Sharon A.
Published: March 2024

Abstract
Metastasis is the leading cause of death in patients with osteosarcoma, the most common pediatric bone malignancy. We conducted a multistage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified an SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P = 1.2 × 10−9; OR, 2.43; 95% confidence interval, 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. In addition, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib and with lowered NFIB expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis and that NFIB is an osteosarcoma metastasis susceptibility gene.

Significance: Metastasis at diagnosis in osteosarcoma is the leading cause of death in these patients. Here we show data that are supportive for the NFIB locus as associated with metastatic potential in osteosarcoma. Cancer Discov; 5(9); 920–31. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 893
Data from Evolution of Neoantigen Landscape during Immune Checkpoint Blockade in Non–Small Cell Lung Cancer
Authors: Anagnostou Valsamo , Smith Kellie N. , Forde Patrick M. , Niknafs Noushin , Bhattacharya Rohit , White James , Zhang Theresa , Adleff Vilmos , Phallen Jillian , Wali Neha , Hruban Carolyn , Guthrie Violeta B. , Rodgers Kristen , Naidoo Jarushka , Kang Hyunseok , Sharfman William , Georgiades Christos , Verde Franco , Illei Peter , Li Qing Kay , Gabrielson Edward , Brock Malcolm V. , Zahnow Cynthia A. , Baylin Stephen B. , Scharpf Robert B. , Brahmer Julie R. , Karchin Rachel , Pardoll Drew M. , Velculescu Victor E.
Published: March 2024

Abstract
Immune checkpoint inhibitors have shown significant therapeutic responses against tumors containing increased mutation-associated neoantigen load. We have examined the evolving landscape of tumor neoantigens during the emergence of acquired resistance in patients with non–small cell lung cancer after initial response to immune checkpoint blockade with anti–PD-1 or anti–PD-1/anti–CTLA-4 antibodies. Analyses of matched pretreatment and resistant tumors identified genomic changes resulting in loss of 7 to 18 putative mutation-associated neoantigens in resistant clones. Peptides generated from the eliminated neoantigens elicited clonal T-cell expansion in autologous T-cell cultures, suggesting that they generated functional immune responses. Neoantigen loss occurred through elimination of tumor subclones or through deletion of chromosomal regions containing truncal alterations, and was associated with changes in T-cell receptor clonality. These analyses provide insight into the dynamics of mutational landscapes during immune checkpoint blockade and have implications for the development of immune therapies that target tumor neoantigens.

Significance: Acquired resistance to immune checkpoint therapy is being recognized more commonly. This work demonstrates for the first time that acquired resistance to immune checkpoint blockade can arise in association with the evolving landscape of mutations, some of which encode tumor neoantigens recognizable by T cells. These observations imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance. Cancer Discov; 7(3); 264–76. ©2017 AACR.

See related commentary by Yang, p. 250.

This article is highlighted in the In This Issue feature, p. 235
Data from Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine
Authors: Pauli Chantal , Hopkins Benjamin D. , Prandi Davide , Shaw Reid , Fedrizzi Tarcisio , Sboner Andrea , Sailer Verena , Augello Michael , Puca Loredana , Rosati Rachele , McNary Terra J. , Churakova Yelena , Cheung Cynthia , Triscott Joanna , Pisapia David , Rao Rema , Mosquera Juan Miguel , Robinson Brian , Faltas Bishoy M. , Emerling Brooke E. , Gadi Vijayakrishna K. , Bernard Brady , Elemento Olivier , Beltran Himisha , Demichelis Francesca , Kemp Christopher J. , Grandori Carla , Cantley Lewis C. , Rubin Mark A.
Published: March 2024

Abstract
Precision medicine is an approach that takes into account the influence of individuals' genes, environment, and lifestyle exposures to tailor interventions. Here, we describe the development of a robust precision cancer care platform that integrates whole-exome sequencing with a living biobank that enables high-throughput drug screens on patient-derived tumor organoids. To date, 56 tumor-derived organoid cultures and 19 patient-derived xenograft (PDX) models have been established from the 769 patients enrolled in an Institutional Review Board–approved clinical trial. Because genomics alone was insufficient to identify therapeutic options for the majority of patients with advanced disease, we used high-throughput drug screening to discover effective treatment strategies. Analysis of tumor-derived cells from four cases, two uterine malignancies and two colon cancers, identified effective drugs and drug combinations that were subsequently validated using 3-D cultures and PDX models. This platform thereby promotes the discovery of novel therapeutic approaches that can be assessed in clinical trials and provides personalized therapeutic options for individual patients where standard clinical options have been exhausted.

Significance: Integration of genomic data with drug screening from personalized in vitro and in vivo cancer models guides precision cancer care and fuels next-generation research. Cancer Discov; 7(5); 462–77. ©2017 AACR.

See related commentary by Picco and Garnett, p. 456.

This article is highlighted in the In This Issue feature, p. 443
Data from Combination Targeted Therapy to Disrupt Aberrant Oncogenic Signaling and Reverse Epigenetic Dysfunction in IDH2- and TET2-Mutant Acute Myeloid Leukemia
Authors: Shih Alan H. , Meydan Cem , Shank Kaitlyn , Garrett-Bakelman Francine E. , Ward Patrick S. , Intlekofer Andrew M. , Nazir Abbas , Stein Eytan M. , Knapp Kristina , Glass Jacob , Travins Jeremy , Straley Kim , Gliser Camelia , Mason Christopher E. , Yen Katharine , Thompson Craig B. , Melnick Ari , Levine Ross L.
Published: March 2024

Abstract
Genomic studies in acute myeloid leukemias (AML) have identified mutations that drive altered DNA methylation, including TET2 and IDH2. Here, we show that models of AML resulting from TET2 or IDH2 mutations combined with FLT3ITD mutations are sensitive to 5-azacytidine or to the IDH2 inhibitor AG-221, respectively. 5-azacytidine and AG-221 treatment induced an attenuation of aberrant DNA methylation and transcriptional output and resulted in a reduction in leukemic blasts consistent with antileukemic activity. These therapeutic benefits were associated with restoration of leukemic cell differentiation, and the normalization of hematopoiesis was derived from mutant cells. By contrast, combining AG-221 or 5-azacytidine with FLT3 inhibition resulted in a reduction in mutant allele burden, progressive recovery of normal hematopoiesis from non-mutant stem-progenitor cells, and reversal of dysregulated DNA methylation and transcriptional output. Together, our studies suggest combined targeting of signaling and epigenetic pathways can increase therapeutic response in AML.

Significance: AMLs with mutations in TET2 or IDH2 are sensitive to epigenetic therapy through inhibition of DNA methyltransferase activity by 5-azacytidine or inhibition of mutant IDH2 through AG-221. These inhibitors induce a differentiation response and can be used to inform mechanism-based combination therapy. Cancer Discov; 7(5); 494–505. ©2017 AACR.

See related commentary by Thomas and Majeti, p. 459.

See related article by Yen et al., p. 478.

This article is highlighted in the In This Issue feature, p. 443