bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from MECP2 Is a Frequently Amplified Oncogene with a Novel Epigenetic Mechanism That Mimics the Role of Activated RAS in Malignancy
Authors: Neupane Manish , Clark Allison P. , Landini Serena , Birkbak Nicolai J. , Eklund Aron C. , Lim Elgene , Culhane Aedin C. , Barry William T. , Schumacher Steven E. , Beroukhim Rameen , Szallasi Zoltan , Vidal Marc , Hill David E. , Silver Daniel P.
Published: April 2023

Abstract
An unbiased genome-scale screen for unmutated genes that drive cancer growth when overexpressed identified methyl cytosine-guanine dinucleotide (CpG) binding protein 2 (MECP2) as a novel oncogene. MECP2 resides in a region of the X-chromosome that is significantly amplified across 18% of cancers, and many cancer cell lines have amplified, overexpressed MECP2 and are dependent on MECP2 expression for growth. MECP2 copy-number gain and RAS family member alterations are mutually exclusive in several cancer types. The MECP2 splicing isoforms activate the major growth factor pathways targeted by activated RAS, the MAPK and PI3K pathways. MECP2 rescued the growth of a KRASG12C-addicted cell line after KRAS downregulation, and activated KRAS rescues the growth of an MECP2-addicted cell line after MECP2 downregulation. MECP2 binding to the epigenetic modification 5-hydroxymethylcytosine is required for efficient transformation. These observations suggest that MECP2 is a commonly amplified oncogene with an unusual epigenetic mode of action.

Significance:MECP2 is a commonly amplified oncogene in human malignancies with a unique epigenetic mechanism of action. Cancer Discov; 6(1); 45–58. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1
Data from CD74–NRG1 Fusions in Lung Adenocarcinoma
Authors: Fernandez-Cuesta Lynnette , Plenker Dennis , Osada Hirotaka , Sun Ruping , Menon Roopika , Leenders Frauke , Ortiz-Cuaran Sandra , Peifer Martin , Bos Marc , Daßler Juliane , Malchers Florian , Schöttle Jakob , Vogel Wenzel , Dahmen Ilona , Koker Mirjam , Ullrich Roland T. , Wright Gavin M. , Russell Prudence A. , Wainer Zoe , Solomon Benjamin , Brambilla Elisabeth , Nagy-Mignotte Hélène , Moro-Sibilot Denis , Brambilla Christian G. , Lantuejoul Sylvie , Altmüller Janine , Becker Christian , Nürnberg Peter , Heuckmann Johannes M. , Stoelben Erich , Petersen Iver , Clement Joachim H. , Sänger Jörg , Muscarella Lucia A. , la Torre Annamaria , Fazio Vito M. , Lahortiga Idoya , Perera Timothy , Ogata Souichi , Parade Marc , Brehmer Dirk , Vingron Martin , Heukamp Lukas C. , Buettner Reinhard , Zander Thomas , Wolf Jürgen , Perner Sven , Ansén Sascha , Haas Stefan A. , Yatabe Yasushi , Thomas Roman K.
Published: April 2023

Abstract
We discovered a novel somatic gene fusion, CD74–NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74–NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2–ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (P < 0.0001). Ectopic expression of CD74–NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K–AKT pathway, and led to increased colony formation in soft agar. Thus, CD74–NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment.

Significance: CD74–NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov; 4(4); 415–22. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 377
Data from CDKN2B Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma
Authors: McNeal Andrew S. , Liu Kevin , Nakhate Vihang , Natale Christopher A. , Duperret Elizabeth K. , Capell Brian C. , Dentchev Tzvete , Berger Shelley L. , Herlyn Meenhard , Seykora John T. , Ridky Todd W.
Published: April 2023

Abstract
Deletion of the entire CDKN2B–CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear. Here, we show that CDKN2B is highly upregulated in benign melanocytic nevi, contributes to maintaining nevus melanocytes in a growth-arrested premalignant state, and is commonly lost in melanoma. Using primary melanocytes isolated directly from freshly excised human nevi naturally expressing the common BRAFV600E-activating mutation, nevi progressing to melanoma, and normal melanocytes engineered to inducibly express BRAFV600E, we show that BRAF activation results in reversible, TGFβ-dependent, p15 induction that halts proliferation. Furthermore, we engineer human skin grafts containing nevus-derived melanocytes to establish a new, architecturally faithful, in vivo melanoma model, and demonstrate that p15 loss promotes the transition from benign nevus to melanoma.

Significance: Although BRAFV600E mutations cause melanocytes to initially proliferate into benign moles, mechanisms responsible for their eventual growth arrest are unknown. Using melanocytes from human moles, we show that BRAF activation leads to a CDKN2B induction that is critical for restraining BRAF oncogenic effects, and when lost, contributes to melanoma. Cancer Discov; 5(10); 1072–85. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 1005
Data from Mutant KRAS–Induced Expression of ICAM-1 in Pancreatic Acinar Cells Causes Attraction of Macrophages to Expedite the Formation of Precancerous Lesions
Authors: Liou Geou-Yarh , Döppler Heike , Necela Brian , Edenfield Brandy , Zhang Lizhi , Dawson David W. , Storz Peter
Published: April 2023

Abstract
Desmoplasia and an inflammatory environment are defining features of pancreatic cancer. Unclear is how pancreatic cells that undergo oncogenic transformation can cross-talk with immune cells and how this contributes to the development of pancreatic lesions. Here, we demonstrate that pancreatic acinar cells expressing mutant KRAS can expedite their transformation to a duct-like phenotype by inducing local inflammation. Specifically, we show that KRASG12D induces the expression of intercellular adhesion molecule-1 (ICAM-1), which serves as chemoattractant for macrophages. Infiltrating macrophages amplify the formation of KRASG12D-caused abnormal pancreatic structures by remodeling the extracellular matrix and providing cytokines such as TNF. Depletion of macrophages or treatment with a neutralizing antibody for ICAM-1 in mice expressing oncogenic Kras under an acinar cell–specific promoter resulted in both a decreased formation of abnormal structures and decreased progression of acinar-to-ductal metaplasia to pancreatic intraepithelial neoplastic lesions.

Significance: We here show that oncogenic KRAS in pancreatic acinar cells upregulates the expression of ICAM-1 to attract macrophages. Hence, our results reveal a direct cooperative mechanism between oncogenic Kras mutations and the inflammatory environment to drive the initiation of pancreatic cancer. Cancer Discov; 5(1); 52–63. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 1
Data from Inflammatory Myofibroblastic Tumors Harbor Multiple Potentially Actionable Kinase Fusions
Authors: Lovly Christine M. , Gupta Abha , Lipson Doron , Otto Geoff , Brennan Tina , Chung Catherine T. , Borinstein Scott C. , Ross Jeffrey S. , Stephens Philip J. , Miller Vincent A. , Coffin Cheryl M.
Published: April 2023

Abstract
Inflammatory myofibroblastic tumor (IMT) is a neoplasm that typically occurs in children. The genetic landscape of this tumor is incompletely understood and therapeutic options are limited. Although 50% of IMTs harbor anaplastic lymphoma kinase (ALK) rearrangements, no therapeutic targets have been identified in ALK-negative tumors. We report for the first time that IMTs harbor other actionable targets, including ROS1 and PDGFRβ fusions. We detail the case of an 8-year-old boy with treatment-refractory ALK-negative IMT. Molecular tumor profiling revealed a ROS1 fusion, and he had a dramatic response to the ROS1 inhibitor crizotinib. This case prompted assessment of a larger series of IMTs. Next-generation sequencing revealed that 85% of cases evaluated harbored kinase fusions involving ALK, ROS1, or PDGFRβ. Our study represents the most comprehensive genetic analysis of IMTs to date and also provides a rationale for routine molecular profiling of these tumors to detect therapeutically actionable kinase fusions.

Significance: Our study describes the most comprehensive genomics-based evaluation of IMT to date. Because there is no “standard-of-care” therapy for IMT, the identification of actionable genomic alterations, in addition to ALK, is expected to redefine management strategies for patients with this disease. Cancer Discov; 4(8); 889–95. ©2014 AACR.

See related commentary by Le and Doebele, p. 870

This article is highlighted in the In This Issue feature, p. 855
Data from Activation of MET via Diverse Exon 14 Splicing Alterations Occurs in Multiple Tumor Types and Confers Clinical Sensitivity to MET Inhibitors
Authors: Frampton Garrett M. , Ali Siraj M. , Rosenzweig Mark , Chmielecki Juliann , Lu Xinyuan , Bauer Todd M. , Akimov Mikhail , Bufill Jose A. , Lee Carrie , Jentz David , Hoover Rick , Ou Sai-Hong Ignatius , Salgia Ravi , Brennan Tim , Chalmers Zachary R. , Jaeger Savina , Huang Alan , Elvin Julia A. , Erlich Rachel , Fichtenholtz Alex , Gowen Kyle A. , Greenbowe Joel , Johnson Adrienne , Khaira Depinder , McMahon Caitlin , Sanford Eric M. , Roels Steven , White Jared , Greshock Joel , Schlegel Robert , Lipson Doron , Yelensky Roman , Morosini Deborah , Ross Jeffrey S. , Collisson Eric , Peters Malte , Stephens Philip J. , Miller Vincent A.
Published: April 2023

Abstract
Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting.

Significance: Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors. Cancer Discov; 5(8); 850–9. ©2015 AACR.

See related commentary by Ma, p. 802.

See related article by Paik et al., p. 842.

This article is highlighted in the In This Issue feature, p. 783
Data from Rapid Induction of Apoptosis by PI3K Inhibitors Is Dependent upon Their Transient Inhibition of RAS–ERK Signaling
Authors: Will Marie , Qin Alice Can Ran , Toy Weiyi , Yao Zhan , Rodrik-Outmezguine Vanessa , Schneider Claudia , Huang Xiaodong , Monian Prashant , Jiang Xuejun , de Stanchina Elisa , Baselga José , Liu Ningshu , Chandarlapaty Sarat , Rosen Neal
Published: April 2023

Abstract
The effects of selective phosphoinositide 3-kinase (PI3K) and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of receptor tyrosine kinases, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild-type RAS and of RAF–MEK–ERK signaling. Inhibition of RAS–ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death, and in murine models of HER2+ cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regression. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity.

Significance: We show that the RAS–ERK pathway is a key downstream effector pathway of oncogenic PI3K. Coordinate downregulation of AKT and ERK is necessary for induction of apoptosis and antitumor activity and can be accomplished with pulsatile dosing, which will likely decrease toxicity and allow administration of therapeutic doses. Cancer Discov; 4(3); 334–47. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 259
Data from Activation of the PD-1 Pathway Contributes to Immune Escape in EGFR-Driven Lung Tumors
Authors: Akbay Esra A. , Koyama Shohei , Carretero Julian , Altabef Abigail , Tchaicha Jeremy H. , Christensen Camilla L. , Mikse Oliver R. , Cherniack Andrew D. , Beauchamp Ellen M. , Pugh Trevor J. , Wilkerson Matthew D. , Fecci Peter E. , Butaney Mohit , Reibel Jacob B. , Soucheray Margaret , Cohoon Travis J. , Janne Pasi A. , Meyerson Matthew , Hayes D. Neil , Shapiro Geoffrey I. , Shimamura Takeshi , Sholl Lynette M. , Rodig Scott J. , Freeman Gordon J. , Hammerman Peter S. , Dranoff Glenn , Wong Kwok-Kin
Published: April 2023

Abstract
The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non–small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition.

Significance: We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non–cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape. Cancer Discov; 3(12); 1355–63. ©2013 AACR.

See related commentary by Rech and Vonderheide, p. 1330

This article is highlighted in the In This Issue feature, p. 1317
Data from Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer
Authors: Bahcall Magda , Sim Taebo , Paweletz Cloud P. , Patel Jyoti D. , Alden Ryan S. , Kuang Yanan , Sacher Adrian G. , Kim Nam Doo , Lydon Christine A. , Awad Mark M. , Jaklitsch Michael T. , Sholl Lynette M. , Jänne Pasi A. , Oxnard Geoffrey R.
Published: April 2023

Abstract
Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non–small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped, and understanding of mechanisms of resistance to MET TKIs is limited. Here, we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that METD1228V induces resistance to type I MET TKIs through impaired drug binding, while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response.

Significance: With several structurally distinct MET inhibitors undergoing development for treatment of NSCLC, it is critical to identify mechanism-based therapies for drug resistance. We demonstrate that an acquired METD1228V mutation mediates resistance to type I, but not type II, MET inhibitors, having therapeutic implications for the clinical use of sequential MET inhibitors. Cancer Discov; 6(12); 1334–41. ©2016 AACR.

See related commentary by Trusolino, p. 1306.

This article is highlighted in the In This Issue feature, p. 1293
Data from The AMPK-Related Kinases SIK1 and SIK3 Mediate Key Tumor-Suppressive Effects of LKB1 in NSCLC
Authors: Hollstein Pablo E. , Eichner Lillian J. , Brun Sonja N. , Kamireddy Anwesh , Svensson Robert U. , Vera Liliana I. , Ross Debbie S. , Rymoff T.J. , Hutchins Amanda , Galvez Hector M. , Williams April E. , Shokhirev Maxim N. , Screaton Robert A. , Berdeaux Rebecca , Shaw Reuben J.
Published: April 2023

Abstract
Mutations in the LKB1 (also known as STK11) tumor suppressor are the third most frequent genetic alteration in non–small cell lung cancer (NSCLC). LKB1 encodes a serine/threonine kinase that directly phosphorylates and activates 14 AMPK family kinases (“AMPKRs”). The function of many of the AMPKRs remains obscure, and which are most critical to the tumor-suppressive function of LKB1 remains unknown. Here, we combine CRISPR and genetic analysis of the AMPKR family in NSCLC cell lines and mouse models, revealing a surprising critical role for the SIK subfamily. Conditional genetic loss of Sik1 revealed increased tumor growth in mouse models of Kras-dependent lung cancer, which was further enhanced by loss of the related kinase Sik3. As most known substrates of the SIKs control transcription, gene-expression analysis was performed, revealing upregulation of AP1 and IL6 signaling in common between LKB1- and SIK1/3-deficient tumors. The SIK substrate CRTC2 was required for this effect, as well as for proliferation benefits from SIK loss.
Significance:
The tumor suppressor LKB1/STK11 encodes a serine/threonine kinase frequently inactivated in NSCLC. LKB1 activates 14 downstream kinases in the AMPK family controlling growth and metabolism, although which kinases are critical for LKB1 tumor-suppressor function has remained an enigma. Here we unexpectedly found that two understudied kinases, SIK1 and SIK3, are critical targets in lung cancer.

This article is highlighted in the In This Issue feature, p. 1469
Data from In Vivo E2F Reporting Reveals Efficacious Schedules of MEK1/2–CDK4/6 Targeting and mTOR–S6 Resistance Mechanisms
Authors: Teh Jessica L.F. , Cheng Phil F. , Purwin Timothy J. , Nikbakht Neda , Patel Prem , Chervoneva Inna , Ertel Adam , Fortina Paolo M. , Kleiber Ines , HooKim Kim , Davies Michael A. , Kwong Lawrence N. , Levesque Mitch P. , Dummer Reinhard , Aplin Andrew E.
Published: April 2023

Abstract
Targeting cyclin-dependent kinases 4/6 (CDK4/6) represents a therapeutic option in combination with BRAF inhibitor and/or MEK inhibitor (MEKi) in melanoma; however, continuous dosing elicits toxicities in patients. Using quantitative and temporal in vivo reporting, we show that continuous MEKi with intermittent CDK4/6 inhibitor (CDK4/6i) led to more complete tumor responses versus other combination schedules. Nevertheless, some tumors acquired resistance that was associated with enhanced phosphorylation of ribosomal S6 protein. These data were supported by phospho-S6 staining of melanoma biopsies from patients treated with CDK4/6i plus targeted inhibitors. Enhanced phospho-S6 in resistant tumors provided a therapeutic window for the mTORC1/2 inhibitor AZD2014. Mechanistically, upregulation or mutation of NRAS was associated with resistance in in vivo models and patient samples, respectively, and mutant NRAS was sufficient to enhance resistance. This study utilizes an in vivo reporter model to optimize schedules and supports targeting mTORC1/2 to overcome MEKi plus CDK4/6i resistance.

Significance: Mutant BRAF and NRAS melanomas acquire resistance to combined MEK and CDK4/6 inhibition via upregulation of mTOR pathway signaling. This resistance mechanism provides the preclinical basis to utilize mTORC1/2 inhibitors to improve MEKi plus CDK4/6i drug regimens. Cancer Discov; 8(5); 568–81. ©2018 AACR.

See related commentary by Sullivan, p. 532.

See related article by Romano et al., p. 556.

This article is highlighted in the In This Issue feature, p. 517
Data from Immunotherapy Resistance by Inflammation-Induced Dedifferentiation
Authors: Mehta Arnav , Kim Yeon Joo , Robert Lidia , Tsoi Jennifer , Comin-Anduix Begoña , Berent-Maoz Beata , Cochran Alistair J. , Economou James S. , Tumeh Paul C. , Puig-Saus Cristina , Ribas Antoni
Published: April 2023

Abstract
A promising arsenal of targeted and immunotherapy treatments for metastatic melanoma has emerged over the last decade. With these therapies, we now face new mechanisms of tumor-acquired resistance. We report here a patient whose metastatic melanoma underwent dedifferentiation as a resistance mechanism to adoptive T-cell transfer therapy (ACT) to the MART1 antigen, a phenomenon that had been observed only in mouse studies to date. After an initial period of tumor regression, the patient presented in relapse with tumors lacking melanocytic antigens (MART1, gp100) and expressing an inflammation-induced neural crest marker (NGFR). We demonstrate using human melanoma cell lines that this resistance phenotype can be induced in vitro by treatment with MART1 T cell receptor–expressing T cells or with TNFα, and that the phenotype is reversible with withdrawal of inflammatory stimuli. This supports the hypothesis that acquired resistance to cancer immunotherapy can be mediated by inflammation-induced cancer dedifferentiation.

Significance: We report a patient whose metastatic melanoma underwent inflammation-induced dedifferentiation as a resistance mechanism to ACT to the MART1 antigen. Our results suggest that future melanoma ACT protocols may benefit from the simultaneous targeting of multiple tumor antigens, modulating the inflammatory response, and inhibition of inflammatory dedifferentiation-inducing signals. Cancer Discov; 8(8); 935–43. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 899
Data from Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers
Authors: Drilon Alexander , Somwar Romel , Mangatt Biju P. , Edgren Henrik , Desmeules Patrice , Ruusulehto Anja , Smith Roger S. , Delasos Lukas , Vojnic Morana , Plodkowski Andrew J. , Sabari Joshua , Ng Kenneth , Montecalvo Joseph , Chang Jason , Tai Huichun , Lockwood William W. , Martinez Victor , Riely Gregory J. , Rudin Charles M. , Kris Mark G. , Arcila Maria E. , Matheny Christopher , Benayed Ryma , Rekhtman Natasha , Ladanyi Marc , Ganji Gopinath
Published: April 2023

Abstract
NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3–ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers.

Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686–95. ©2018 AACR.

See related commentary by Wilson and Politi, p. 676.

This article is highlighted in the In This Issue feature, p. 663
Data from Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation
Authors: Gachet Stéphanie , El-Chaar Tiama , Avran David , Genesca Eulalia , Catez Frédéric , Quentin Samuel , Delord Marc , Thérizols Gabriel , Briot Delphine , Meunier Godelieve , Hernandez Lucie , Pla Marika , Smits Willem K. , Buijs-Gladdines Jessica G. , Van Loocke Wouter , Menschaert Gerben , André-Schmutz Isabelle , Taghon Tom , Van Vlierberghe Pieter , Meijerink Jules P. , Baruchel André , Dombret Hervé , Clappier Emmanuelle , Diaz Jean-Jacques , Gazin Claude , de Thé Hugues , Sigaux François , Soulier Jean
Published: April 2023

Abstract
Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a Tal1/Lmo1/Notch1-driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression.
Significance:
The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome–mitochondria axis, suggesting the potential for therapeutic intervention.

This article is highlighted in the In This Issue feature, p. 1494
Data from KEAP1/NFE2L2 Mutations Predict Lung Cancer Radiation Resistance That Can Be Targeted by Glutaminase Inhibition
Authors: Binkley Michael S. , Jeon Young-Jun , Nesselbush Monica , Moding Everett J. , Nabet Barzin Y. , Almanza Diego , Kunder Christian , Stehr Henning , Yoo Christopher H. , Rhee Siyeon , Xiang Michael , Chabon Jacob J. , Hamilton Emily , Kurtz David M. , Gojenola Linda , Owen Susie Grant , Ko Ryan B. , Shin June Ho , Maxim Peter G. , Lui Natalie S. , Backhus Leah M. , Berry Mark F. , Shrager Joseph B. , Ramchandran Kavitha J. , Padda Sukhmani K. , Das Millie , Neal Joel W. , Wakelee Heather A. , Alizadeh Ash A. , Loo Billy W. , Diehn Maximilian
Published: April 2023

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

This article is highlighted in the In This Issue feature, p. 1775
Data from The Landscape of Human Cancer Proteins Targeted by SARS-CoV-2
Authors: Tutuncuoglu Beril , Cakir Merve , Batra Jyoti , Bouhaddou Mehdi , Eckhardt Manon , Gordon David E. , Krogan Nevan J.
Published: April 2023

AbstractSummary:
The mapping of SARS-CoV-2 human protein–protein interactions by Gordon and colleagues revealed druggable targets that are hijacked by the virus. Here, we highlight several oncogenic pathways identified at the host–virus interface of SARS-CoV-2 to enable cancer biologists to apply their knowledge for rapid drug repurposing to treat COVID-19, and help inform the response to potential long-term complications of the disease.
Data from Exploiting the Therapeutic Interaction of WNT Pathway Activation and Asparaginase for Colorectal Cancer Therapy
Authors: Hinze Laura , Labrosse Roxane , Degar James , Han Teng , Schatoff Emma M. , Schreek Sabine , Karim Salmaan , McGuckin Connor , Sacher Joshua R. , Wagner Florence , Stanulla Martin , Yuan Chen , Sicinska Ewa , Giannakis Marios , Ng Kimmie , Dow Lukas E. , Gutierrez Alejandro
Published: April 2023

Abstract
Colorectal cancer is driven by mutations that activate canonical WNT/β-catenin signaling, but inhibiting WNT has significant on-target toxicity, and there are no approved therapies targeting dominant oncogenic drivers. We recently found that activating a β-catenin–independent branch of WNT signaling that inhibits GSK3-dependent protein degradation induces asparaginase sensitivity in drug-resistant leukemias. To test predictions from our model, we turned to colorectal cancer because these cancers can have WNT-activating mutations that function either upstream (i.e., R-spondin fusions) or downstream (APC or β-catenin mutations) of GSK3, thus allowing WNT/β-catenin and WNT-induced asparaginase sensitivity to be unlinked genetically. We found that asparaginase had little efficacy in APC or β-catenin–mutant colorectal cancer, but was profoundly toxic in the setting of R-spondin fusions. Pharmacologic GSK3α inhibition was sufficient for asparaginase sensitization in APC or β-catenin–mutant colorectal cancer, but not in normal intestinal progenitors. Our findings demonstrate that WNT-induced therapeutic vulnerabilities can be exploited for colorectal cancer therapy.
Significance:
Solid tumors are thought to be asparaginase-resistant via de novo asparagine synthesis. In leukemia, GSK3α-dependent protein degradation, a catabolic amino acid source, mediates asparaginase resistance. We found that asparaginase is profoundly toxic to colorectal cancers with WNT-activating mutations that inhibit GSK3. Aberrant WNT activation can provide a therapeutic vulnerability in colorectal cancer.

See related commentary by Davidsen and Sullivan, p. 1632.

This article is highlighted in the In This Issue feature, p. 1611
Data from Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities
Authors: Kelly Marcus R. , Kostyrko Kaja , Han Kyuho , Mooney Nancie A. , Jeng Edwin E. , Spees Kaitlyn , Dinh Phuong T. , Abbott Keene L. , Gwinn Dana M. , Sweet-Cordero E. Alejandro , Bassik Michael C. , Jackson Peter K.
Published: April 2023

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

This article is highlighted in the In This Issue feature, p. 1775
Data from Case Fatality Rate of Cancer Patients with COVID-19 in a New York Hospital System
Authors: Mehta Vikas , Goel Sanjay , Kabarriti Rafi , Cole Daniel , Goldfinger Mendel , Acuna-Villaorduna Ana , Pradhan Kith , Thota Raja , Reissman Stan , Sparano Joseph A. , Gartrell Benjamin A. , Smith Richard V. , Ohri Nitin , Garg Madhur , Racine Andrew D. , Kalnicki Shalom , Perez-Soler Roman , Halmos Balazs , Verma Amit
Published: April 2023

Abstract
Patients with cancer are presumed to be at increased risk from COVID-19 infection–related fatality due to underlying malignancy, treatment-related immunosuppression, or increased comorbidities. A total of 218 COVID-19–positive patients from March 18, 2020, to April 8, 2020, with a malignant diagnosis were identified. A total of 61 (28%) patients with cancer died from COVID-19 with a case fatality rate (CFR) of 37% (20/54) for hematologic malignancies and 25% (41/164) for solid malignancies. Six of 11 (55%) patients with lung cancer died from COVID-19 disease. Increased mortality was significantly associated with older age, multiple comorbidities, need for ICU support, and elevated levels of D-dimer, lactate dehydrogenase, and lactate in multivariate analysis. Age-adjusted CFRs in patients with cancer compared with noncancer patients at our institution and New York City reported a significant increase in case fatality for patients with cancer. These data suggest the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population.
Significance:
COVID-19 in patients with cancer is associated with a significantly increased risk of case fatality, suggesting the need for proactive strategies to reduce likelihood of infection and improve early identification in this vulnerable patient population.

This article is highlighted in the In This Issue feature, p. 890
Data from The Evolutionary Origins of Recurrent Pancreatic Cancer
Authors: Sakamoto Hitomi , Attiyeh Marc A. , Gerold Jeffrey M. , Makohon-Moore Alvin P. , Hayashi Akimasa , Hong Jungeui , Kappagantula Rajya , Zhang Lance , Melchor Jerry P. , Reiter Johannes G. , Heyde Alexander , Bielski Craig M. , Penson Alexander V. , Gönen Mithat , Chakravarty Debyani , O'Reilly Eileen M. , Wood Laura D. , Hruban Ralph H. , Nowak Martin A. , Socci Nicholas D. , Taylor Barry S. , Iacobuzio-Donahue Christine A.
Published: April 2023

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

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

This article is highlighted in the In This Issue feature, p. 747
Data from Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer
Authors: Fong Lawrence , Hotson Andrew , Powderly John D. , Sznol Mario , Heist Rebecca S. , Choueiri Toni K. , George Saby , Hughes Brett G.M. , Hellmann Matthew D. , Shepard Dale R. , Rini Brian I. , Kummar Shivaani , Weise Amy M. , Riese Matthew J. , Markman Ben , Emens Leisha A. , Mahadevan Daruka , Luke Jason J. , Laport Ginna , Brody Joshua D. , Hernandez-Aya Leonel , Bonomi Philip , Goldman Jonathan W. , Berim Lyudmyla , Renouf Daniel J. , Goodwin Rachel A. , Munneke Brian , Ho Po Y. , Hsieh Jessica , McCaffery Ian , Kwei Long , Willingham Stephen B. , Miller Richard A.
Published: April 2023

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

See related commentary by Sitkovsky, p. 16.

This article is highlighted in the In This Issue feature, p. 1
Data from Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma
Authors: Aoki Tomohiro , Chong Lauren C. , Takata Katsuyoshi , Milne Katy , Hav Monirath , Colombo Anthony , Chavez Elizabeth A. , Nissen Michael , Wang Xuehai , Miyata-Takata Tomoko , Lam Vivian , Viganò Elena , Woolcock Bruce W. , Telenius Adèle , Li Michael Y. , Healy Shannon , Ghesquiere Chanel , Kos Daniel , Goodyear Talia , Veldman Johanna , Zhang Allen W. , Kim Jubin , Saberi Saeed , Ding Jiarui , Farinha Pedro , Weng Andrew P. , Savage Kerry J. , Scott David W. , Krystal Gerald , Nelson Brad H. , Mottok Anja , Merchant Akil , Shah Sohrab P. , Steidl Christian
Published: April 2023

Abstract
Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma–specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma–associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class II–deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma.
Significance:
We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell–like immunosuppressive subset of LAG3+ T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints.

See related commentary by Fisher and Oh, p. 342.

This article is highlighted in the In This Issue feature, p. 327
Data from Overcoming Genetically Based Resistance Mechanisms to PD-1 Blockade
Authors: Torrejon Davis Y. , Abril-Rodriguez Gabriel , Champhekar Ameya S. , Tsoi Jennifer , Campbell Katie M. , Kalbasi Anusha , Parisi Giulia , Zaretsky Jesse M. , Garcia-Diaz Angel , Puig-Saus Cristina , Cheung-Lau Gardenia , Wohlwender Thomas , Krystofinski Paige , Vega-Crespo Agustin , Lee Christopher M. , Mascaro Pau , Grasso Catherine S. , Berent-Maoz Beata , Comin-Anduix Begoña , Hu-Lieskovan Siwen , Ribas Antoni
Published: April 2023

Abstract
Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti–PD-1 therapy in vivo. JAK1/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti–PD-1, mediated by natural killer (NK) and CD8 T cells. B2M-knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy.
Significance:
The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy.

This article is highlighted in the In This Issue feature, p. 1079
Data from EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer
Authors: Amodio Vito , Yaeger Rona , Arcella Pamela , Cancelliere Carlotta , Lamba Simona , Lorenzato Annalisa , Arena Sabrina , Montone Monica , Mussolin Benedetta , Bian Yu , Whaley Adele , Pinnelli Marika , Murciano-Goroff Yonina R. , Vakiani Efsevia , Valeri Nicola , Liao Wei-Li , Bhalkikar Anuja , Thyparambil Sheeno , Zhao Hui-Yong , de Stanchina Elisa , Marsoni Silvia , Siena Salvatore , Bertotti Andrea , Trusolino Livio , Li Bob T. , Rosen Neal , Di Nicolantonio Federica , Bardelli Alberto , Misale Sandra
Published: April 2023

Abstract
Most patients with KRASG12C–mutant non–small cell lung cancer (NSCLC) experience clinical benefit from selective KRASG12C inhibition, whereas patients with colorectal cancer bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRASG12C inhibitors in colorectal cancer, we examined the effects of AMG510 in KRASG12C colorectal cancer cell lines. Unlike NSCLC cell lines, KRASG12C colorectal cancer models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In colorectal cancer lines, KRASG12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRASG12C blockade, we identify EGFR signaling as the dominant mechanism of colorectal cancer resistance to KRASG12C inhibitors. The combinatorial targeting of EGFR and KRASG12C is highly effective in colorectal cancer cells and patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat patients with KRASG12C colorectal cancer.
Significance:
The efficacy of KRASG12C inhibitors in NSCLC and colorectal cancer is lineage-specific. RTK dependency and signaling rebound kinetics are responsible for sensitivity or resistance to KRASG12C inhibition in colorectal cancer. EGFR and KRASG12C should be concomitantly inhibited to overcome resistance to KRASG12C blockade in colorectal tumors.

See related commentary by Koleilat and Kwong, p. 1094.

This article is highlighted in the In This Issue feature, p. 1079