bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies
Authors: Jordan Emmet J. , Kim Hyunjae R. , Arcila Maria E. , Barron David , Chakravarty Debyani , Gao JianJiong , Chang Matthew T. , Ni Andy , Kundra Ritika , Jonsson Philip , Jayakumaran Gowtham , Gao Sizhi Paul , Johnsen Hannah C. , Hanrahan Aphrothiti J. , Zehir Ahmet , Rekhtman Natasha , Ginsberg Michelle S. , Li Bob T. , Yu Helena A. , Paik Paul K. , Drilon Alexander , Hellmann Matthew D. , Reales Dalicia N. , Benayed Ryma , Rusch Valerie W. , Kris Mark G. , Chaft Jamie E. , Baselga José , Taylor Barry S. , Schultz Nikolaus , Rudin Charles M. , Hyman David M. , Berger Michael F. , Solit David B. , Ladanyi Marc , Riely Gregory J.
Published: March 2024

Abstract
Tumor genetic testing is standard of care for patients with advanced lung adenocarcinoma, but the fraction of patients who derive clinical benefit remains undefined. Here, we report the experience of 860 patients with metastatic lung adenocarcinoma analyzed prospectively for mutations in >300 cancer-associated genes. Potentially actionable genetic events were stratified into one of four levels based upon published clinical or laboratory evidence that the mutation in question confers increased sensitivity to standard or investigational therapies. Overall, 37.1% (319/860) of patients received a matched therapy guided by their tumor molecular profile. Excluding alterations associated with standard-of-care therapy, 14.4% (69/478) received matched therapy, with a clinical benefit of 52%. Use of matched therapy was strongly influenced by the level of preexistent clinical evidence that the mutation identified predicts for drug response. Analysis of genes mutated significantly more often in tumors without known actionable mutations nominated STK11 and KEAP1 as possible targetable mitogenic drivers.

Significance: An increasing number of therapies that target molecular alterations required for tumor maintenance and progression have demonstrated clinical activity in patients with lung adenocarcinoma. The data reported here suggest that broader, early testing for molecular alterations that have not yet been recognized as standard-of-care predictive biomarkers of drug response could accelerate the development of targeted agents for rare mutational events and could result in improved clinical outcomes. Cancer Discov; 7(6); 596–609. ©2017 AACR.

See related commentary by Liu et al., p. 555.

This article is highlighted in the In This Issue feature, p. 539
Data from Acquired Initiating Mutations in Early Hematopoietic Cells of CLL Patients
Authors: Damm Frederik , Mylonas Elena , Cosson Adrien , Yoshida Kenichi , Della Valle Véronique , Mouly Enguerran , Diop M'boyba , Scourzic Laurianne , Shiraishi Yuichi , Chiba Kenichi , Tanaka Hiroko , Miyano Satoru , Kikushige Yoshikane , Davi Frederick , Lambert Jérôme , Gautheret Daniel , Merle-Béral Hélène , Sutton Laurent , Dessen Philippe , Solary Eric , Akashi Koichi , Vainchenker William , Mercher Thomas , Droin Nathalie , Ogawa Seishi , Nguyen-Khac Florence , Bernard Olivier A.
Published: March 2024

Abstract
Appropriate cancer care requires a thorough understanding of the natural history of the disease, including the cell of origin, the pattern of clonal evolution, and the functional consequences of the mutations. Using deep sequencing of flow-sorted cell populations from patients with chronic lymphocytic leukemia (CLL), we established the presence of acquired mutations in multipotent hematopoietic progenitors. Mutations affected known lymphoid oncogenes, including BRAF, NOTCH1, and SF3B1. NFKBIE and EGR2 mutations were observed at unexpectedly high frequencies, 10.7% and 8.3% of 168 advanced-stage patients, respectively. EGR2 mutations were associated with a shorter time to treatment and poor overall survival. Analyses of BRAF and EGR2 mutations suggest that they result in deregulation of B-cell receptor (BCR) intracellular signaling. Our data propose disruption of hematopoietic and early B-cell differentiation through the deregulation of pre-BCR signaling as a phenotypic outcome of CLL mutations and show that CLL develops from a pre-leukemic phase.

Significance: The origin and pathogenic mechanisms of CLL are not fully understood. The current work indicates that CLL develops from pre-leukemic multipotent hematopoietic progenitors carrying somatic mutations. It advocates for abnormalities in early B-cell differentiation as a phenotypic convergence of the diverse acquired mutations observed in CLL. Cancer Discov; 4(9); 1088–1101. ©2014 AACR.

See related commentary by Jiang and Elemento, p. 995

This article is highlighted in the In This Issue feature, p. 973
Data from Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations
Authors: Drilon Alexander , Ou Sai-Hong Ignatius , Cho Byoung Chul , Kim Dong-Wan , Lee Jeeyun , Lin Jessica J. , Zhu Viola W. , Ahn Myung-Ju , Camidge D. Ross , Nguyen Judy , Zhai Dayong , Deng Wei , Huang Zhongdong , Rogers Evan , Liu Juliet , Whitten Jeff , Lim John K. , Stopatschinskaja Shanna , Hyman David M. , Doebele Robert C. , Cui J. Jean , Shaw Alice T.
Published: March 2024

Abstract
The use of tyrosine kinase inhibitors (TKI) with activity against ALK, ROS1, or TRKA–C can result in significant clinical benefit in patients with diverse tumors harboring ALK, ROS1, or NTRK1–3 rearrangements; however, resistance invariably develops. The emergence of on-target kinase domain mutations represents a major mechanism of acquired resistance. Solvent-front substitutions such as ALKG1202R, ROS1G2032R or ROS1D2033N, TRKAG595R, and TRKCG623R are among the most recalcitrant of these mechanisms. Repotrectinib (TPX-0005) is a rationally designed, low-molecular-weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA–C, and ALK. Importantly, repotrectinib exhibits activity against a variety of solvent-front substitutions in vitro and in vivo. As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with ROS1 or NTRK3 fusion–positive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance.

Significance: Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1–3, and ALK. Repotrectinib may represent an effective therapeutic option for patients with ROS1-, NTRK1–3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs. Cancer Discov; 8(10); 1227–36. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1195
Data from Discovery and Optimization of HKT288, a Cadherin-6–Targeting ADC for the Treatment of Ovarian and Renal Cancers
Authors: Bialucha Carl U. , Collins Scott D. , Li Xiao , Saxena Parmita , Zhang Xiamei , Dürr Clemens , Lafont Bruno , Prieur Pierric , Shim Yeonju , Mosher Rebecca , Lee David , Ostrom Lance , Hu Tiancen , Bilic Sanela , Rajlic Ivana Liric , Capka Vladimir , Jiang Wei , Wagner Joel P. , Elliott GiNell , Veloso Artur , Piel Jessica C. , Flaherty Meghan M. , Mansfield Keith G. , Meseck Emily K. , Rubic-Schneider Tina , London Anne Serdakowski , Tschantz William R. , Kurz Markus , Nguyen Duc , Bourret Aaron , Meyer Matthew J. , Faris Jason E. , Janatpour Mary J. , Chan Vivien W. , Yoder Nicholas C. , Catcott Kalli C. , McShea Molly A. , Sun Xiuxia , Gao Hui , Williams Juliet , Hofmann Francesco , Engelman Jeffrey A. , Ettenberg Seth A. , Sellers William R. , Lees Emma
Published: March 2024

Abstract
Despite an improving therapeutic landscape, significant challenges remain in treating the majority of patients with advanced ovarian or renal cancer. We identified the cell–cell adhesion molecule cadherin-6 (CDH6) as a lineage gene having significant differential expression in ovarian and kidney cancers. HKT288 is an optimized CDH6-targeting DM4-based antibody–drug conjugate (ADC) developed for the treatment of these diseases. Our study provides mechanistic evidence supporting the importance of linker choice for optimal antitumor activity and highlights CDH6 as an antigen for biotherapeutic development. To more robustly predict patient benefit of targeting CDH6, we incorporate a population-based patient-derived xenograft (PDX) clinical trial (PCT) to capture the heterogeneity of response across an unselected cohort of 30 models—a novel preclinical approach in ADC development. HKT288 induces durable tumor regressions of ovarian and renal cancer models in vivo, including 40% of models on the PCT, and features a preclinical safety profile supportive of progression toward clinical evaluation.

Significance: We identify CDH6 as a target for biotherapeutics development and demonstrate how an integrated pharmacology strategy that incorporates mechanistic pharmacodynamics and toxicology studies provides a rich dataset for optimizing the therapeutic format. We highlight how a population-based PDX clinical trial and retrospective biomarker analysis can provide correlates of activity and response to guide initial patient selection for first-in-human trials of HKT288. Cancer Discov; 7(9); 1030–45. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 920
Data from SHP2 Inhibition Prevents Adaptive Resistance to MEK Inhibitors in Multiple Cancer Models
Authors: Fedele Carmine , Ran Hao , Diskin Brian , Wei Wei , Jen Jayu , Geer Mitchell J. , Araki Kiyomi , Ozerdem Ugur , Simeone Diane M. , Miller George , Neel Benjamin G. , Tang Kwan Ho
Published: March 2024

Abstract
Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 (PTPN11) is required for RAS/ERK pathway activation by most RTKs and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEKi inhibited the proliferation of multiple cancer cell lines in vitro. PTPN11 knockdown/MEKi treatment had similar effects, whereas expressing SHP099 binding–defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target. SHP099/trametinib was highly efficacious in xenograft and/or genetically engineered models of KRAS-mutant pancreas, lung, and ovarian cancers and in wild-type RAS-expressing triple-negative breast cancer. SHP099 inhibited activation of KRAS mutants with residual GTPase activity, impeded SOS/RAS/MEK/ERK1/2 reactivation in response to MEKi, and blocked ERK1/2-dependent transcriptional programs. We conclude that SHP099/MEKi combinations could have therapeutic utility in multiple malignancies.

Significance: MEK inhibitors show limited efficacy as single agents, in part because of the rapid development of adaptive resistance. We find that SHP2/MEK inhibitor combinations prevent adaptive resistance in multiple cancer models expressing mutant and wild-type KRAS. Cancer Discov; 8(10); 1237–49. ©2018 AACR.

See related commentary by Torres-Ayuso and Brognard, p. 1210.

This article is highlighted in the In This Issue feature, p. 1195
Data from Prediction of DNA Repair Inhibitor Response in Short-Term Patient-Derived Ovarian Cancer Organoids
Authors: Hill Sarah J. , Decker Brennan , Roberts Emma A. , Horowitz Neil S. , Muto Michael G. , Worley Michael J. , Feltmate Colleen M. , Nucci Marisa R. , Swisher Elizabeth M. , Nguyen Huy , Yang Chunyu , Morizane Ryuji , Kochupurakkal Bose S. , Do Khanh T. , Konstantinopoulos Panagiotis A. , Liu Joyce F. , Bonventre Joseph V. , Matulonis Ursula A. , Shapiro Geoffrey I. , Berkowitz Ross S. , Crum Christopher P. , D'Andrea Alan D.
Published: March 2024

Abstract
Based on genomic analysis, 50% of high-grade serous ovarian cancers (HGSC) are predicted to have DNA repair defects. Whether this substantial subset of HGSCs actually have functional repair defects remains unknown. Here, we devise a platform for functional profiling of DNA repair in short-term patient-derived HGSC organoids. We tested 33 organoid cultures derived from 22 patients with HGSC for defects in homologous recombination (HR) and replication fork protection. Regardless of DNA repair gene mutational status, a functional defect in HR in the organoids correlated with PARP inhibitor sensitivity. A functional defect in replication fork protection correlated with carboplatin and CHK1 and ATR inhibitor sensitivity. Our results indicate that a combination of genomic analysis and functional testing of organoids allows for the identification of targetable DNA damage repair defects. Larger numbers of patient-derived organoids must be analyzed to determine whether these assays can reproducibly predict patient response in the clinic.

Significance: Patient-derived ovarian tumor organoids grow rapidly and match the tumors from which they are derived, both genetically and functionally. These organoids can be used for DNA repair profiling and therapeutic sensitivity testing and provide a rapid means of assessing targetable defects in the parent tumor, offering more suitable treatment options. Cancer Discov; 8(11); 1404–21. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1333
Data from First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study
Authors: Sullivan Ryan J. , Infante Jeffrey R. , Janku Filip , Wong Deborah Jean Lee , Sosman Jeffrey A. , Keedy Vicki , Patel Manish R. , Shapiro Geoffrey I. , Mier James W. , Tolcher Anthony W. , Wang-Gillam Andrea , Sznol Mario , Flaherty Keith , Buchbinder Elizabeth , Carvajal Richard D. , Varghese Anna M. , Lacouture Mario E. , Ribas Antoni , Patel Sapna P. , DeCrescenzo Gary A. , Emery Caroline M. , Groover Anna L. , Saha Saurabh , Varterasian Mary , Welsch Dean J. , Hyman David M. , Li Bob T.
Published: March 2024

Abstract
Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600–, and non–V600 BRAF-mutant solid tumors.

Significance: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600–mutant solid-tumor malignancies. Cancer Discov; 8(2); 184–95. ©2017 AACR.

See related commentary by Smalley and Smalley, p. 140.

This article is highlighted in the In This Issue feature, p. 127
Data from Gut Microbiota Promotes Obesity-Associated Liver Cancer through PGE2-Mediated Suppression of Antitumor Immunity
Authors: Loo Tze Mun , Kamachi Fumitaka , Watanabe Yoshihiro , Yoshimoto Shin , Kanda Hiroaki , Arai Yuriko , Nakajima-Takagi Yaeko , Iwama Atsushi , Koga Tomoaki , Sugimoto Yukihiko , Ozawa Takayuki , Nakamura Masaru , Kumagai Miho , Watashi Koichi , Taketo Makoto M. , Aoki Tomohiro , Narumiya Shuh , Oshima Masanobu , Arita Makoto , Hara Eiji , Ohtani Naoko
Published: March 2024

Abstract
Obesity increases the risk of cancers, including hepatocellular carcinomas (HCC). However, the precise molecular mechanisms through which obesity promotes HCC development are still unclear. Recent studies have shown that gut microbiota may influence liver diseases by transferring its metabolites and components. Here, we show that the hepatic translocation of obesity-induced lipoteichoic acid (LTA), a Gram-positive gut microbial component, promotes HCC development by creating a tumor-promoting microenvironment. LTA enhances the senescence-associated secretory phenotype (SASP) of hepatic stellate cells (HSC) collaboratively with an obesity-induced gut microbial metabolite, deoxycholic acid, to upregulate the expression of SASP factors and COX2 through Toll-like receptor 2. Interestingly, COX2-mediated prostaglandin E2 (PGE2) production suppresses the antitumor immunity through a PTGER4 receptor, thereby contributing to HCC progression. Moreover, COX2 overexpression and excess PGE2 production were detected in HSCs in human HCCs with noncirrhotic, nonalcoholic steatohepatitis (NASH), indicating that a similar mechanism could function in humans.

Significance: We showed the importance of the gut–liver axis in obesity-associated HCC. The gut microbiota–driven COX2 pathway produced the lipid mediator PGE2 in senescent HSCs in the tumor microenvironment, which plays a pivotal role in suppressing antitumor immunity, suggesting that PGE2 and its receptor may be novel therapeutic targets for noncirrhotic NASH-associated HCC. Cancer Discov; 7(5); 522–38. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 443
Data from AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer
Authors: Cross Darren A.E. , Ashton Susan E. , Ghiorghiu Serban , Eberlein Cath , Nebhan Caroline A. , Spitzler Paula J. , Orme Jonathon P. , Finlay M. Raymond V. , Ward Richard A. , Mellor Martine J. , Hughes Gareth , Rahi Amar , Jacobs Vivien N. , Brewer Monica Red , Ichihara Eiki , Sun Jing , Jin Hailing , Ballard Peter , Al-Kadhimi Katherine , Rowlinson Rachel , Klinowska Teresa , Richmond Graham H.P. , Cantarini Mireille , Kim Dong-Wan , Ranson Malcolm R. , Pao William
Published: March 2024

Abstract
First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm+) non–small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino–pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm+ and EGFRm+/T790M+ mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm+ T790M+ NSCLC is described as proof of principle.

Significance: We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M+ mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented. Cancer Discov; 4(9); 1046–61. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 973
Data from In Situ Vaccination with a TLR9 Agonist and Local Low-Dose Radiation Induces Systemic Responses in Untreated Indolent Lymphoma
Authors: Frank Matthew J. , Reagan Patrick M. , Bartlett Nancy L. , Gordon Leo I. , Friedberg Jonathan W. , Czerwinski Debra K. , Long Steven R. , Hoppe Richard T. , Janssen Robert , Candia Albert F. , Coffman Robert L. , Levy Ronald
Published: March 2024

Abstract
This multicenter phase I/II clinical trial evaluated intratumoral SD-101, a TLR9 agonist, and low-dose radiation in patients with untreated indolent lymphoma. Twenty-nine enrolled patients received 4 Gy of radiation followed by 5 weekly intratumoral injections of SD-101 at a single tumor site. No treatment-related grade 4 or serious adverse events occurred. Nearly all patients had tumor reduction at their treated site. More importantly, 24 patients had tumor reduction at their nontreated sites, with 5 patients achieving a partial response and one achieving a complete response. Treatment-related increases of CD8+ and CD4+ effector T cells and decreases of T follicular helper and T regulatory cells (Treg) were observed in the tumor microenvironment. Low pretreatment levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells were associated with favorable outcomes. Intratumoral SD-101 in combination with low-dose radiation is well tolerated and results in regression of both treated and untreated sites of disease.

Significance: In situ vaccination with the TLR9 agonist SD-101, along with low-dose radiation, was safe and induced systemic responses in patients with indolent lymphoma. Low levels of CD4+ Tregs, proliferating CD8+ T cells, and Granzyme B+ CD8+ T cells in the tumor microenvironment predicted favorable response to treatment. Cancer Discov; 8(10); 1258–69. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1195
Data from TOX Regulates Growth, DNA Repair, and Genomic Instability in T-cell Acute Lymphoblastic Leukemia
Authors: Lobbardi Riadh , Pinder Jordan , Martinez-Pastor Barbara , Theodorou Marina , Blackburn Jessica S. , Abraham Brian J. , Namiki Yuka , Mansour Marc , Abdelfattah Nouran S. , Molodtsov Aleksey , Alexe Gabriela , Toiber Debra , de Waard Manon , Jain Esha , Boukhali Myriam , Lion Mattia , Bhere Deepak , Shah Khalid , Gutierrez Alejandro , Stegmaier Kimberly , Silverman Lewis B. , Sadreyev Ruslan I. , Asara John M. , Oettinger Marjorie A. , Haas Wilhelm , Look A. Thomas , Young Richard A. , Mostoslavsky Raul , Dellaire Graham , Langenau David M.
Published: March 2024

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Using a transgenic screen in zebrafish, thymocyte selection–associated high mobility group box protein (TOX) was uncovered as a collaborating oncogenic driver that accelerated T-ALL onset by expanding the initiating pool of transformed clones and elevating genomic instability. TOX is highly expressed in a majority of human T-ALL and is required for proliferation and continued xenograft growth in mice. Using a wide array of functional analyses, we uncovered that TOX binds directly to KU70/80 and suppresses recruitment of this complex to DNA breaks to inhibit nonhomologous end joining (NHEJ) repair. Impaired NHEJ is well known to cause genomic instability, including development of T-cell malignancies in KU70- and KU80-deficient mice. Collectively, our work has uncovered important roles for TOX in regulating NHEJ by elevating genomic instability during leukemia initiation and sustaining leukemic cell proliferation following transformation.

Significance: TOX is an HMG box–containing protein that has important roles in T-ALL initiation and maintenance. TOX inhibits the recruitment of KU70/KU80 to DNA breaks, thereby inhibiting NHEJ repair. Thus, TOX is likely a dominant oncogenic driver in a large fraction of human T-ALL and enhances genomic instability. Cancer Discov; 7(11); 1336–53. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1201
Data from Patient-Derived Xenograft Models: An Emerging Platform for Translational Cancer Research
Authors: Hidalgo Manuel , Amant Frederic , Biankin Andrew V. , Budinská Eva , Byrne Annette T. , Caldas Carlos , Clarke Robert B. , de Jong Steven , Jonkers Jos , Mælandsmo Gunhild Mari , Roman-Roman Sergio , Seoane Joan , Trusolino Livio , Villanueva Alberto
Published: March 2024

Abstract
Recently, there has been an increasing interest in the development and characterization of patient-derived tumor xenograft (PDX) models for cancer research. PDX models mostly retain the principal histologic and genetic characteristics of their donor tumor and remain stable across passages. These models have been shown to be predictive of clinical outcomes and are being used for preclinical drug evaluation, biomarker identification, biologic studies, and personalized medicine strategies. This article summarizes the current state of the art in this field, including methodologic issues, available collections, practical applications, challenges and shortcomings, and future directions, and introduces a European consortium of PDX models.

Significance: PDX models are increasingly used in translational cancer research. These models are useful for drug screening, biomarker development, and the preclinical evaluation of personalized medicine strategies. This review provides a timely overview of the key characteristics of PDX models and a detailed discussion of future directions in the field. Cancer Discov; 4(9); 998–1013. ©2014 AACR.
Data from High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial
Authors: Massard Christophe , Michiels Stefan , Ferté Charles , Le Deley Marie-Cécile , Lacroix Ludovic , Hollebecque Antoine , Verlingue Loic , Ileana Ecaterina , Rosellini Silvia , Ammari Samy , Ngo-Camus Maud , Bahleda Rastislav , Gazzah Anas , Varga Andrea , Postel-Vinay Sophie , Loriot Yohann , Even Caroline , Breuskin Ingrid , Auger Nathalie , Job Bastien , De Baere Thierry , Deschamps Frederic , Vielh Philippe , Scoazec Jean-Yves , Lazar Vladimir , Richon Catherine , Ribrag Vincent , Deutsch Eric , Angevin Eric , Vassal Gilles , Eggermont Alexander , André Fabrice , Soria Jean-Charles
Published: March 2024

Abstract
High-throughput genomic analyses may improve outcomes in patients with advanced cancers. MOSCATO 01 is a prospective clinical trial evaluating the clinical benefit of this approach. Nucleic acids were extracted from fresh-frozen tumor biopsies and analyzed by array comparative genomic hybridization, next-generation sequencing, and RNA sequencing. The primary objective was to evaluate clinical benefit as measured by the percentage of patients presenting progression-free survival (PFS) on matched therapy (PFS2) 1.3-fold longer than the PFS on prior therapy (PFS1). A total of 1,035 adult patients were included, and a biopsy was performed in 948. An actionable molecular alteration was identified in 411 of 843 patients with a molecular portrait. A total of 199 patients were treated with a targeted therapy matched to a genomic alteration. The PFS2/PFS1 ratio was >1.3 in 33% of the patients (63/193). Objective responses were observed in 22 of 194 patients (11%; 95% CI, 7%–17%), and median overall survival was 11.9 months (95% CI, 9.5–14.3 months).

Significance: This study suggests that high-throughput genomics could improve outcomes in a subset of patients with hard-to-treat cancers. Although these results are encouraging, only 7% of the successfully screened patients benefited from this approach. Randomized trials are needed to validate this hypothesis and to quantify the magnitude of benefit. Expanding drug access could increase the percentage of patients who benefit. Cancer Discov; 7(6); 586–95. ©2017 AACR.

See related commentary by Schram and Hyman, p. 552.

This article is highlighted in the In This Issue feature, p. 539
Data from Defining Key Signaling Nodes and Therapeutic Biomarkers in NF1-Mutant Cancers
Authors: Malone Clare F. , Fromm Jody A. , Maertens Ophélia , DeRaedt Thomas , Ingraham Rachel , Cichowski Karen
Published: March 2024

Abstract
NF1 encodes a RAS GTPase-activating protein. Accordingly, aberrant RAS activation underlies the pathogenesis of NF1-mutant cancers. Nevertheless, it is unclear which RAS pathway components represent optimal therapeutic targets. Here, we identify mTORC1 as the key PI3K effector in NF1-mutant nervous system malignancies and conversely show that mTORC2 and AKT are dispensable. However, we find that tumor regression requires sustained inhibition of both mTORC1 and MEK. Transcriptional profiling studies were therefore used to establish a signature of effective mTORC1–MEK inhibition in vivo. We unexpectedly found that the glucose transporter GLUT1 was potently suppressed, but only when both pathways were inhibited. Moreover, unlike VHL- and LKB1-mutant cancers, reduction of 18F-FDG uptake required the suppression of both mTORC1 and MEK. Together, these studies identify optimal and suboptimal therapeutic targets in NF1-mutant malignancies and define a noninvasive means of measuring combined mTORC1–MEK inhibition in vivo, which can be readily incorporated into clinical trials.

Significance: This work demonstrates that mTORC1 and MEK are key therapeutic targets in NF1-mutant cancers and establishes a noninvasive biomarker of effective, combined target inhibition that can be evaluated in clinical trials. Cancer Discov; 4(9); 1062–73. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 973
Data from MEF2C Phosphorylation Is Required for Chemotherapy Resistance in Acute Myeloid Leukemia
Authors: Brown Fiona C. , Still Eric , Koche Richard P. , Yim Christina Y. , Takao Sumiko , Cifani Paolo , Reed Casie , Gunasekera Shehana , Ficarro Scott B. , Romanienko Peter , Mark Willie , McCarthy Craig , de Stanchina Elisa , Gonen Mithat , Seshan Venkatraman , Bhola Patrick , O'Donnell Conor , Spitzer Barbara , Stutzke Crystal , Lavallée Vincent-Philippe , Hébert Josée , Krivtsov Andrei V. , Melnick Ari , Paietta Elisabeth M. , Tallman Martin S. , Letai Anthony , Sauvageau Guy , Pouliot Gayle , Levine Ross , Marto Jarrod A , Armstrong Scott A. , Kentsis Alex
Published: March 2024

Abstract
In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2cS222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL–AF9. MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells. Treatment with the selective MARK/SIK inhibitor MRT199665 caused apoptosis and conferred chemosensitivity in MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease.

Significance: Functional proteomics identifies phosphorylation of MEF2C in the majority of primary chemotherapy-resistant AML. Kinase-dependent dysregulation of this transcription factor confers susceptibility to MARK/SIK kinase inhibition in preclinical models, substantiating its clinical investigation for improved diagnosis and therapy of AML. Cancer Discov; 8(4); 478–97. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 371
Data from Transcriptomic Profiling of the Tumor Microenvironment Reveals Distinct Subgroups of Clear Cell Renal Cell Cancer: Data from a Randomized Phase III Trial
Authors: Hakimi A. Ari , Voss Martin H. , Kuo Fengshen , Sanchez Alejandro , Liu Ming , Nixon Briana G. , Vuong Lynda , Ostrovnaya Irina , Chen Ying-Bei , Reuter Victor , Riaz Nadeem , Cheng Yuan , Patel Parul , Marker Mahtab , Reising Albert , Li Ming O. , Chan Timothy A. , Motzer Robert J.
Published: March 2024

Abstract
Metastasis remains the main reason for renal cell carcinoma (RCC)–associated mortality. Tyrosine kinase inhibitors (TKI) impart clinical benefit for most patients with RCC, but the determinants of response are poorly understood. We report an integrated genomic and transcriptomic analysis of patients with metastatic clear cell RCC (ccRCC) treated with TKI therapy and identify predictors of response. Patients in the COMPARZ phase III trial received first-line sunitinib or pazopanib with comparable efficacy. RNA-based analyses revealed four distinct molecular subgroups associated with response and survival. Characterization of these subgroups identified mutation profiles, angiogenesis, and macrophage infiltration programs to be powerful predictors of outcome with TKI therapy. Notably, predictors differed by the type of TKI received. Our study emphasizes the clinical significance of angiogenesis and immune tumor microenvironment and suggests that the critical effects its various aspects have on TKI efficacy vary by agent. This has broad implications for optimizing precision treatment of RCC.
Significance:
The determinants of response to TKI therapy in metastatic ccRCC remain unknown. Our study demonstrates that key angiogenic and immune profiles of the tumor microenvironment may affect TKI response. These findings have the potential to inform treatment personalization in patients with RCC.

This article is highlighted in the In This Issue feature, p. 453
Data from NRG1 Fusions in KRAS Wild-Type Pancreatic Cancer
Authors: Heining Christoph , Horak Peter , Uhrig Sebastian , Codo Paula L. , Klink Barbara , Hutter Barbara , Fröhlich Martina , Bonekamp David , Richter Daniela , Steiger Katja , Penzel Roland , Endris Volker , Ehrenberg Karl Roland , Frank Stephanie , Kleinheinz Kortine , Toprak Umut H. , Schlesner Matthias , Mandal Ranadip , Schulz Lothar , Lambertz Helmut , Fetscher Sebastian , Bitzer Michael , Malek Nisar P. , Horger Marius , Giese Nathalia A. , Strobel Oliver , Hackert Thilo , Springfeld Christoph , Feuerbach Lars , Bergmann Frank , Schröck Evelin , von Kalle Christof , Weichert Wilko , Scholl Claudia , Ball Claudia R. , Stenzinger Albrecht , Brors Benedikt , Fröhling Stefan , Glimm Hanno
Published: March 2024

Abstract
We used whole-genome and transcriptome sequencing to identify clinically actionable genomic alterations in young adults with pancreatic ductal adenocarcinoma (PDAC). Molecular characterization of 17 patients with PDAC enrolled in a precision oncology program revealed gene fusions amenable to pharmacologic inhibition by small-molecule tyrosine kinase inhibitors in all patients with KRAS wild-type (KRASWT) tumors (4 of 17). These alterations included recurrent NRG1 rearrangements predicted to drive PDAC development through aberrant ERBB receptor–mediated signaling, and pharmacologic ERBB inhibition resulted in clinical improvement and remission of liver metastases in 2 patients with NRG1-rearranged tumors that had proved resistant to standard treatment. Our findings demonstrate that systematic screening of KRASWT tumors for oncogenic fusion genes will substantially improve the therapeutic prospects for a sizeable fraction of patients with PDAC.

Significance: Advanced PDAC is a malignancy with few treatment options that lacks molecular mechanism-based therapies. Our study uncovers recurrent gene rearrangements such as NRG1 fusions as disease-driving events in KRASwt tumors, thereby providing novel insights into oncogenic signaling and new therapeutic options in this entity. Cancer Discov; 8(9); 1087–95. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 1047
Data from Targeted Therapies for Targeted Populations: Anti-EGFR Treatment for EGFR-Amplified Gastroesophageal Adenocarcinoma
Authors: Maron Steven B. , Alpert Lindsay , Kwak Heewon A. , Lomnicki Samantha , Chase Leah , Xu David , O'Day Emily , Nagy Rebecca J. , Lanman Richard B. , Cecchi Fabiola , Hembrough Todd , Schrock Alexa , Hart John , Xiao Shu-Yuan , Setia Namrata , Catenacci Daniel V.T.
Published: March 2024

Abstract
Previous anti-EGFR trials in unselected patients with gastroesophageal adenocarcinoma (GEA) were resoundingly negative. We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven patients received ≥1 dose of treatment: three first-line FOLFOX plus ABT-806, one second-line FOLFIRI plus cetuximab, and three third/fourth-line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pretreatment and posttreatment tumor next-generation sequencing (NGS), serial plasma circulating tumor DNA (ctDNA) NGS, and tumor IHC/FISH for EGFR revealed preexisting and/or acquired genomic events, including EGFR-negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC, and HER2 amplification, and GNAS mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3+ infiltrate, including one who demonstrated increased NKp46+, and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action. EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged.

Significance: This paper highlights the role of EGFR inhibitors in EGFR-amplified GEA—despite negative results in prior unselected phase III trials. Using serial ctDNA and tissue NGS, we identified mechanisms of primary and acquired resistance in all patients, as well as potential contribution of antibody-dependent cell-mediated cytotoxicity to their clinical benefit. Cancer Discov; 8(6); 696–713. ©2018 AACR.

See related commentary by Strickler, p. 679.

This article is highlighted in the In This Issue feature, p. 663
Data from EGFR-Mediated Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib
Authors: Corcoran Ryan B. , Ebi Hiromichi , Turke Alexa B. , Coffee Erin M. , Nishino Michiya , Cogdill Alexandria P. , Brown Ronald D. , Della Pelle Patricia , Dias-Santagata Dora , Hung Kenneth E. , Flaherty Keith T. , Piris Adriano , Wargo Jennifer A. , Settleman Jeffrey , Mino-Kenudson Mari , Engelman Jeffrey A.
Published: March 2024

Abstract
BRAF mutations occur in 10% to 15% of colorectal cancers and confer adverse outcome in the metastatic setting. Although RAF inhibitors such as vemurafenib (PLX4032) have proven effective in the treatment of BRAF-mutant melanoma, they are surprisingly ineffective in BRAF-mutant colorectal cancers, and the reason for this disparity remains unclear. Compared with BRAF-mutant melanoma cells, BRAF-mutant colorectal cancer cells were less sensitive to vemurafenib, and phospho-extracellular signal-regulated kinase (P-ERK) suppression was not sustained in response to treatment. Although transient inhibition of P-ERK by vemurafenib was observed in colorectal cancer, rapid ERK reactivation occurred through epidermal growth factor receptor (EGFR)-mediated activation of RAS and CRAF. BRAF-mutant colorectal cancers expressed greater levels of phospho-EGFR than BRAF-mutant melanomas, suggesting that colorectal cancers are specifically poised for EGFR-mediated resistance. Combined RAF and EGFR inhibition blocked reactivation of mitogen-activated protein kinase (MAPK) signaling in BRAF-mutant colorectal cancer cells and markedly improved efficacy in vitro and in vivo. These findings support the evaluation of combined RAF and EGFR inhibition in patients with BRAF-mutant colorectal cancer.

Significance: BRAF valine 600 (V600) mutations occur in 10% to 15% of colorectal cancers, yet these tumors show a surprisingly low clinical response rate (∼5%) to selective RAF inhibitors such as vemurafenib, which have produced dramatic response rates (60%–80%) in melanomas harboring the identical BRAF V600 mutation. We found that EGFR-mediated MAPK pathway reactivation leads to resistance to vemurafenib in BRAF-mutant colorectal cancers and that combined RAF and EGFR inhibition can lead to sustained MAPK pathway suppression and improved efficacy in vitro and in tumor xenografts. Cancer Discovery; 2(3); 227–35. ©2012 AACR.

This article is highlighted in the In This Issue feature, p. 193
Data from Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel AKT1 Fusion–Driven Cancer
Authors: Slotkin Emily K. , Diolaiti Daniel , Shukla Neerav N. , Dela Cruz Filemon S. , Clark Jennifer J. , Gundem Gunes , Yellapantula Venkata D. , Levine Max F. , You Daoqi , Ma Peilin , Pachhal Sagarika , Ibanez Sanchez Glorymar , Benayed Ryma , Jungbluth Achim A. , Smyth Lillian M. , Mauguen Audrey , Gushterova Irena , Ding Hongxu , Spraggon Lee , Darnell Robert , Califano Andrea , Ladanyi Marc , Papaemmanuil Elli , Kung Andrew L. , Hyman David M. , Roberts Stephen S.
Published: March 2024

Abstract
Despite the important role of the PI3K/AKT/mTOR axis in the pathogenesis of cancer, to date there have been few functional oncogenic fusions identified involving the AKT genes. A 12-year-old female with a histopathologically indeterminate epithelioid neoplasm was found to harbor a novel fusion between the LAMTOR1 and AKT1 genes. Through expanded use access, she became the first pediatric patient to be treated with the oral ATP-competitive pan-AKT inhibitor ipatasertib. Treatment resulted in dramatic tumor regression, demonstrating through patient-driven discovery that the fusion resulted in activation of AKT1, was an oncogenic driver, and could be therapeutically targeted with clinical benefit. Post-clinical validation using patient-derived model systems corroborated these findings, confirmed a membrane-bound and constitutively active fusion protein, and identified potential mechanisms of resistance to single-agent treatment with ipatasertib.
Significance:
This study describes the patient-driven discovery of the first AKT1 fusion–driven cancer and its treatment with the AKT inhibitor ipatasertib. Patient-derived in vitro and in vivo model systems are used to confirm the LAMTOR1–AKT1 fusion as a tumorigenic driver and identify potential mechanisms of resistance to AKT inhibition.

This article is highlighted in the In This Issue feature, p. 565
Data from EGFR and MET Amplifications Determine Response to HER2 Inhibition in ERBB2-Amplified Esophagogastric Cancer
Authors: Sanchez-Vega Francisco , Hechtman Jaclyn F. , Castel Pau , Ku Geoffrey Y. , Tuvy Yaelle , Won Helen , Fong Christopher J. , Bouvier Nancy , Nanjangud Gouri J. , Soong Joanne , Vakiani Efsevia , Schattner Mark , Kelsen David P. , Lefkowitz Robert A. , Brown Karen , Lacouture Mario E. , Capanu Marinela , Mattar Marissa , Qeriqi Besnik , Cecchi Fabiola , Tian Yuan , Hembrough Todd , Nagy Rebecca J. , Lanman Richard B. , Larson Steven M. , Pandit-Taskar Neeta , Schöder Heiko , Iacobuzio-Donahue Christine A. , Ilson David H. , Weber Wolfgang A. , Berger Michael F. , de Stanchina Elisa , Taylor Barry S. , Lewis Jason S. , Solit David B. , Carrasquillo Jorge A. , Scaltriti Maurizio , Schultz Nikolaus , Janjigian Yelena Y.
Published: March 2024

Abstract
The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with ERBB2 (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of EGFR and ERBB2. Heterogeneous 89Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking EGFR amplification or with acquisition of MET amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in ERBB2 and MET coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in ERBB2-amplified EG cancer.
Significance:
Analysis of patients with ERBB2-amplified, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with EGFR/ERBB2 coamplification and MET amplification, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones.

See related commentary by Klempner and Catenacci, p. 166.

This article is highlighted in the In This Issue feature, p. 151
Data from Notch Shapes the Innate Immunophenotype in Breast Cancer
Authors: Shen Qiang , Cohen Brenda , Zheng Weiyue , Rahbar Ramtin , Martin Bernard , Murakami Kiichi , Lamorte Sara , Thompson Patrycja , Berman Hal , Zúñiga-Pflücker Juan Carlos , Ohashi Pamela S. , Reedijk Michael
Published: March 2024

Abstract
Notch activation, which is associated with basal-like breast cancer (BLBC), normally directs tissue patterning, suggesting that it may shape the tumor microenvironment. Here, we show that Notch in tumor cells regulates the expression of two powerful proinflammatory cytokines, IL1β and CCL2, and the recruitment of tumor-associated macrophages (TAM). Notch also regulates TGFβ-mediated activation of tumor cells by TAMs, closing a Notch-dependent paracrine signaling loop between these two cell types. We use a mouse model in which Notch can be regulated in spontaneous mammary carcinoma to confirm that IL1β and CCL2 production, and macrophage recruitment are Notch-dependent. In human disease, expression array analyses demonstrate a striking association between Notch activation, IL1β and CCL2 production, macrophage infiltration, and BLBC. These findings place Notch at the nexus of a vicious cycle of macrophage infiltration and amplified cytokine secretion and provide immunotherapeutic opportunities in BLBC.

Significance: BLBC is aggressive and has an unmet need for effective targeted treatment. Our data highlight immunotherapeutic opportunities in Notch-activated BLBC. Effective IL1β and CCL2 antagonists are currently in clinical review to treat benign inflammatory disease, and their transition to the cancer clinic could have a rapid impact. Cancer Discov; 7(11); 1320–35. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1201