bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Extrachromosomal DNA Amplification Contributes to Small Cell Lung Cancer Heterogeneity and Is Associated with Worse Outcomes
Authors: Pongor Lőrinc Sándor , Schultz Christopher W. , Rinaldi Lorenzo , Wangsa Darawalee , Redon Christophe E. , Takahashi Nobuyuki , Fialkoff Gavriel , Desai Parth , Zhang Yang , Burkett Sandra , Hermoni Nadav , Vilk Noa , Gutin Jenia , Gergely Rona , Zhao Yongmei , Nichols Samantha , Vilimas Rasa , Sciuto Linda , Graham Chante , Caravaca Juan Manuel , Turan Sevilay , Tsai-wei Shen , Rajapakse Vinodh N. , Kumar Rajesh , Upadhyay Deep , Kumar Suresh , Kim Yoo Sun , Roper Nitin , Tran Bao , Hewitt Stephen M. , Kleiner David E. , Aladjem Mirit I. , Friedman Nir , Hager Gordon L. , Pommier Yves , Ried Thomas , Thomas Anish
Published: April 2023

Abstract
Small-cell lung cancer (SCLC) is an aggressive neuroendocrine lung cancer. Oncogenic MYC amplifications drive SCLC heterogeneity, but the genetic mechanisms of MYC amplification and phenotypic plasticity, characterized by neuroendocrine and nonneuroendocrine cell states, are not known. Here, we integrate whole-genome sequencing, long-range optical mapping, single-cell DNA sequencing, and fluorescence in situ hybridization to find extrachromosomal DNA (ecDNA) as a primary source of SCLC oncogene amplifications and driver fusions. ecDNAs bring to proximity enhancer elements and oncogenes, creating SCLC transcription-amplifying units, driving exceptionally high MYC gene dosage. We demonstrate that cell-free nucleosome profiling can noninvasively detect ecDNA amplifications in plasma, facilitating its genome-wide interrogation in SCLC and other cancers. Altogether, our work provides the first comprehensive map of SCLC ecDNA and describes a new mechanism that governs MYC-driven SCLC heterogeneity. ecDNA-enabled transcriptional flexibility may explain the significantly worse survival outcomes of SCLC harboring complex ecDNA amplifications.
Significance:
MYC drives SCLC progression, but the genetic basis of MYC-driven SCLC evolution is unknown. Using SCLC as a paradigm, we report how ecDNA amplifications function as MYC-amplifying units, fostering tumor plasticity and a high degree of tumor heterogeneity.

This article is highlighted in the In This Issue feature, p. 799
Data from Moving Spatially Resolved Multiplexed Protein Profiling toward Clinical Oncology
Authors: Pourmaleki Maryam , Socci Nicholas D. , Hollmann Travis J. , Mellinghoff Ingo K.
Published: April 2023

Summary:
The shift in cancer therapy from broadly cytotoxic agents toward “personalized” treatments that target specific alterations in each patient's tumor requires diagnostic pathology approaches that are quantitative and biospecimen-friendly. Novel multiplexed antibody-based imaging technologies can measure single-cell expression of over 60 proteins in intact tumor sections and hold promise for clinical oncology.
Data from The Genomic Landscape of Pediatric Ewing Sarcoma
Authors: Crompton Brian D. , Stewart Chip , Taylor-Weiner Amaro , Alexe Gabriela , Kurek Kyle C. , Calicchio Monica L. , Kiezun Adam , Carter Scott L. , Shukla Sachet A. , Mehta Swapnil S. , Thorner Aaron R. , de Torres Carmen , Lavarino Cinzia , Suñol Mariona , McKenna Aaron , Sivachenko Andrey , Cibulskis Kristian , Lawrence Michael S. , Stojanov Petar , Rosenberg Mara , Ambrogio Lauren , Auclair Daniel , Seepo Sara , Blumenstiel Brendan , DeFelice Matthew , Imaz-Rosshandler Ivan , Schwarz-Cruz y Celis Angela , Rivera Miguel N. , Rodriguez-Galindo Carlos , Fleming Mark D. , Golub Todd R. , Getz Gad , Mora Jaume , Stegmaier Kimberly
Published: April 2023

Abstract
Pediatric Ewing sarcoma is characterized by the expression of chimeric fusions of EWS and ETS family transcription factors, representing a paradigm for studying cancers driven by transcription factor rearrangements. In this study, we describe the somatic landscape of pediatric Ewing sarcoma. These tumors are among the most genetically normal cancers characterized to date, with only EWS–ETS rearrangements identified in the majority of tumors. STAG2 loss, however, is present in more than 15% of Ewing sarcoma tumors; occurs by point mutation, rearrangement, and likely nongenetic mechanisms; and is associated with disease dissemination. Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways, highlighting the need for new therapeutic approaches to target EWS–ETS fusions in this disease.

Significance: We performed next-generation sequencing of Ewing sarcoma, a pediatric cancer involving bone, characterized by expression of EWS–ETS fusions. We found remarkably few mutations. However, we discovered that loss of STAG2 expression occurs in 15% of tumors and is associated with metastatic disease, suggesting a potential genetic vulnerability in Ewing sarcoma. Cancer Discov; 4(11); 1326–41. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 1243
Data from RapidCaP, a Novel GEM Model for Metastatic Prostate Cancer Analysis and Therapy, Reveals Myc as a Driver of Pten-Mutant Metastasis
Authors: Cho Hyejin , Herzka Tali , Zheng Wu , Qi Jun , Wilkinson John E. , Bradner James E. , Robinson Brian D. , Castillo-Martin Mireia , Cordon-Cardo Carlos , Trotman Lloyd C.
Published: April 2023

Abstract
Genetically engineered mouse (GEM) models are a pillar of functional cancer research. Here, we developed RapidCaP, a GEM modeling system that uses surgical injection for viral gene delivery to the prostate. We show that in Pten deficiency, loss of p53 suffices to trigger metastasis to distant sites at greater than 50% penetrance by four months, consistent with results from human prostate cancer genome analysis. Live bioluminescence tracking showed that endogenous primary and metastatic disease responds to castration before developing lethal castration resistance. To our surprise, the resulting lesions showed no activation of Akt but activation of the Myc oncogene. Using RapidCaP, we find that Myc drives local prostate metastasis and is critical for maintenance of metastasis, as shown by using the Brd4 inhibitor JQ1. Taken together, our data suggest that a “MYC-switch” away from AKT forms a critical and druggable event in PTEN-mutant prostate cancer metastasis and castration resistance.

Significance: The RapidCaP system introduces fast and flexible genetics for functional analysis and therapy for endogenous metastatic prostate cancer. The approach introduces targeting of MYC as a critical strategy against PTEN-deficient lethal prostate cancer. Cancer Discov; 4(3); 318–33. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 259
Data from The ALK/ROS1 Inhibitor PF-06463922 Overcomes Primary Resistance to Crizotinib in ALK-Driven Neuroblastoma
Authors: Infarinato Nicole R. , Park Jin H. , Krytska Kateryna , Ryles Hannah T. , Sano Renata , Szigety Katherine M. , Li Yimei , Zou Helen Y. , Lee Nathan V. , Smeal Tod , Lemmon Mark A. , Mossé Yael P.
Published: April 2023

Abstract
Neuroblastomas harboring activating point mutations in anaplastic lymphoma kinase (ALK) are differentially sensitive to the ALK inhibitor crizotinib, with certain mutations conferring intrinsic crizotinib resistance. To overcome this clinical obstacle, our goal was to identify inhibitors with improved potency that can target intractable ALK variants such as F1174L. We find that PF-06463922 has high potency across ALK variants and inhibits ALK more effectively than crizotinib in vitro. Most importantly, PF-06463922 induces complete tumor regression in both crizotinib-resistant and crizotinib-sensitive xenograft mouse models of neuroblastoma, as well as in patient-derived xenografts harboring the crizotinib-resistant F1174L or F1245C mutations. These studies demonstrate that PF-06463922 has the potential to overcome crizotinib resistance and exerts unprecedented activity as a single targeted agent against F1174L and F1245C ALK-mutated xenograft tumors, while also inducing responses in an R1275Q xenograft model. Taken together, these results provide the rationale to move PF-06463922 into clinical trials for treatment of patients with ALK-mutated neuroblastoma.

Significance: The next-generation ALK/ROS1 inhibitor PF-06463922 exerts unparalleled activity in ALK-driven neuroblastoma models with primary crizotinib resistance. Our biochemical and in vivo data provide the preclinical rationale for fast-tracking the development of this agent in children with relapsed/refractory ALK-mutant neuroblastoma. Cancer Discov; 6(1); 96–107. ©2015 AACR.

See related commentary by Versteeg and George, p. 20.

This article is highlighted in the In This Issue feature, p. 1
Data from Immune Checkpoint Blockade Enhances Shared Neoantigen-Induced T-cell Immunity Directed against Mutated Calreticulin in Myeloproliferative Neoplasms
Authors: Cimen Bozkus Cansu , Roudko Vladimir , Finnigan John P. , Mascarenhas John , Hoffman Ronald , Iancu-Rubin Camelia , Bhardwaj Nina
Published: April 2023

Abstract
Somatic frameshift mutations in the calreticulin (CALR) gene are key drivers of cellular transformation in myeloproliferative neoplasms (MPN). All patients carrying these mutations (CALR+ MPN) share an identical sequence in the C-terminus of the mutated CALR protein (mut-CALR), with the potential for utility as a shared neoantigen. Here, we demonstrate that although a subset of patients with CALR+ MPN develop specific T-cell responses against the mut-CALR C-terminus, PD-1 or CTLA4 expression abrogates the full complement of responses. Significantly, blockade of PD-1 and CLTA4 ex vivo by mAbs and of PD-1 in vivo by pembrolizumab administration restores mut-CALR–specific T-cell immunity in some patients with CALR+ MPN. Moreover, mut-CALR elicits antigen-specific responses from both CD4+ and CD8+ T cells, confirming its broad applicability as an immunogen. Collectively, these results establish mut-CALR as a shared, MPN-specific neoantigen and inform the design of novel immunotherapies targeting mut-CALR.
Significance:
Current treatment modalities for MPN are not effective in eliminating malignant cells. Here, we show that mutations in the CALR gene, which drive transformation in MPN, elicit T-cell responses that can be further enhanced by checkpoint blockade, suggesting immunotherapies could be employed to eliminate CALR+ malignant cells in MPN.

This article is highlighted in the In This Issue feature, p. 1143
Data from Exploiting MCL1 Dependency with Combination MEK + MCL1 Inhibitors Leads to Induction of Apoptosis and Tumor Regression in KRAS-Mutant Non–Small Cell Lung Cancer
Authors: Nangia Varuna , Siddiqui Faria M. , Caenepeel Sean , Timonina Daria , Bilton Samantha J. , Phan Nicole , Gomez-Caraballo Maria , Archibald Hannah L. , Li Chendi , Fraser Cameron , Rigas Diamanda , Vajda Kristof , Ferris Lorin A. , Lanuti Michael , Wright Cameron D. , Raskin Kevin A. , Cahill Daniel P. , Shin John H. , Keyes Colleen , Sequist Lecia V. , Piotrowska Zofia , Farago Anna F. , Azzoli Christopher G. , Gainor Justin F. , Sarosiek Kristopher A. , Brown Sean P. , Coxon Angela , Benes Cyril H. , Hughes Paul E. , Hata Aaron N.
Published: April 2023

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

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

This article is highlighted in the In This Issue feature, p. 1494
Data from Transcription-Associated Cyclin-Dependent Kinases as Targets and Biomarkers for Cancer Therapy
Authors: Chou Jonathan , Quigley David A. , Robinson Troy M. , Feng Felix Y. , Ashworth Alan
Published: April 2023

Abstract
Drugs targeting the cell cycle–regulatory cyclin-dependent kinase (CDK) 4 and 6 have been approved for the treatment of hormone receptor–positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Another class of CDKs, the transcription-associated CDKs, including CDK7, CDK8, CDK9, CDK12 and CDK13, are critical regulators of gene expression. Recent evidence suggests several novel functions of these CDKs, including regulation of epigenetic modifications, intronic polyadenylation, DNA-damage responses, and genomic stability. Here, we summarize our current understanding of the transcriptional CDKs, their utility as biomarkers, and their potential as therapeutic targets.
Significance:
CDK inhibitors targeting CDK4 and CDK6 have been approved in hormone receptor–positive breast cancer, and inhibitors targeting other cell-cycle CDKs are currently in clinical trials. Several studies now point to potential therapeutic opportunities by inhibiting the transcription-associated CDKs as well as therapeutic vulnerabilities with PARP inhibitors and immunotherapy in tumors deficient in these CDKs.
Data from Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors
Authors: Tsurutani Junji , Iwata Hiroji , Krop Ian , Jänne Pasi A. , Doi Toshihiko , Takahashi Shunji , Park Haeseong , Redfern Charles , Tamura Kenji , Wise-Draper Trisha M. , Saito Kaku , Sugihara Masahiro , Singh Jasmeet , Jikoh Takahiro , Gallant Gilles , Li Bob T.
Published: April 2023

Abstract
HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8–11.1] months. In HER2-mutant non–small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1–14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors.
Significance:
T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs.

See related commentary by Rolfo and Russo, p. 643.

This article is highlighted in the In This Issue feature, p. 627
Data from Pan-Cancer Efficacy of Vemurafenib in BRAFV600-Mutant Non-Melanoma Cancers
Authors: Subbiah Vivek , Puzanov Igor , Blay Jean-Yves , Chau Ian , Lockhart A. Craig , Raje Noopur S. , Wolf Juergen , Baselga José , Meric-Bernstam Funda , Roszik Jason , Diamond Eli L. , Riely Gregory J. , Sherman Eric J. , Riehl Todd , Pitcher Bethany , Hyman David M.
Published: April 2023

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

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

This article is highlighted in the In This Issue feature, p. 627
Data from The Folate Cycle Enzyme MTHFR Is a Critical Regulator of Cell Response to MYC-Targeting Therapies
Authors: Su Angela , Ling Frank , Vaganay Camille , Sodaro Gaetano , Benaksas Chaïma , Dal Bello Reinaldo , Forget Antoine , Pardieu Bryann , Lin Kevin H. , Rutter Justine C. , Bassil Christopher F. , Fortin Gael , Pasanisi Justine , Antony-Debré Iléana , Alexe Gabriela , Benoist Jean-François , Pruvost Alain , Pikman Yana , Qi Jun , Schlageter Marie-Hélène , Micol Jean-Baptiste , Roti Giovanni , Cluzeau Thomas , Dombret Hervé , Preudhomme Claude , Fenouille Nina , Benajiba Lina , Golan Hava M. , Stegmaier Kimberly , Lobry Camille , Wood Kris C. , Itzykson Raphael , Puissant Alexandre
Published: April 2023

Abstract
Deciphering the impact of metabolic intervention on response to anticancer therapy may elucidate a path toward improved clinical responses. Here, we identify amino acid–related pathways connected to the folate cycle whose activation predicts sensitivity to MYC-targeting therapies in acute myeloid leukemia (AML). We establish that folate restriction and deficiency of the rate-limiting folate cycle enzyme MTHFR, which exhibits reduced-function polymorphisms in about 10% of Caucasians, induce resistance to MYC targeting by BET and CDK7 inhibitors in cell lines, primary patient samples, and syngeneic mouse models of AML. Furthermore, this effect is abrogated by supplementation with the MTHFR enzymatic product CH3-THF. Mechanistically, folate cycle disturbance reduces H3K27/K9 histone methylation and activates a SPI1 transcriptional program counteracting the effect of BET inhibition. Our data provide a rationale for screening MTHFR polymorphisms and folate cycle status to nominate patients most likely to benefit from MYC-targeting therapies.
Significance:
Although MYC-targeting therapies represent a promising strategy for cancer treatment, evidence of predictors of sensitivity to these agents is limited. We pinpoint that folate cycle disturbance and frequent polymorphisms associated with reduced MTHFR activity promote resistance to BET inhibitors. CH3-THF supplementation thus represents a low-risk intervention to enhance their effects.

See related commentary by Marando and Huntly, p. 1791.

This article is highlighted in the In This Issue feature, p. 1775
Data from CRISPR-GEMM Pooled Mutagenic Screening Identifies KMT2D as a Major Modulator of Immune Checkpoint Blockade
Authors: Wang Guangchuan , Chow Ryan D. , Zhu Lvyun , Bai Zhigang , Ye Lupeng , Zhang Feifei , Renauer Paul A. , Dong Matthew B. , Dai Xiaoyun , Zhang Xiaoya , Du Yaying , Cheng Yujing , Niu Leilei , Chu Zhiyuan , Kim Kristin , Liao Cun , Clark Paul , Errami Youssef , Chen Sidi
Published: April 2023

Abstract
Immune checkpoint blockade (ICB) has shown remarkable clinical efficacy in several cancer types. However, only a fraction of patients will respond to ICB. Here, we performed pooled mutagenic screening with CRISPR-mediated genetically engineered mouse models (CRISPR-GEMM) in ICB settings, and identified KMT2D as a major modulator of ICB response across multiple cancer types. KMT2D encodes a histone H3K4 methyltransferase and is among the most frequently mutated genes in patients with cancer. Kmt2d loss led to increased DNA damage and mutation burden, chromatin remodeling, intron retention, and activation of transposable elements. In addition, Kmt2d-mutant cells exhibited increased protein turnover and IFNγ-stimulated antigen presentation. In turn, Kmt2d-mutant tumors in both mouse and human were characterized by increased immune infiltration. These data demonstrate that Kmt2d deficiency sensitizes tumors to ICB by augmenting tumor immunogenicity, and also highlight the power of CRISPR-GEMMs for interrogating complex molecular landscapes in immunotherapeutic contexts that preserve the native tumor microenvironment.
Significance:
ICB is ineffective in the majority of patients. Through direct in vivo CRISPR mutagenesis screening in GEMMs of cancer, we find Kmt2d deficiency sensitizes tumors to ICB. Considering the prevalence of KMT2D mutations, this finding potentially has broad implications for patient stratification and clinical decision-making.

This article is highlighted in the In This Issue feature, p. 1775
Data from Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer
Authors: Parker Seth J. , Amendola Caroline R. , Hollinshead Kate E.R. , Yu Qijia , Yamamoto Keisuke , Encarnación-Rosado Joel , Rose Rebecca E. , LaRue Madeleine M. , Sohn Albert S.W. , Biancur Doug E. , Paulo Joao A. , Gygi Steven P. , Jones Drew R. , Wang Huamin , Philips Mark R. , Bar-Sagi Dafna , Mancias Joseph D. , Kimmelman Alec C.
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSC). Previous studies have demonstrated that stromal supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine cross-talk between PSCs and PDAC is orchestrated by the utilization of specific transporters. PSCs utilize SLC1A4 and other transporters to rapidly exchange and maintain environmental alanine concentrations. Moreover, PDAC cells upregulate SLC38A2 to supply their increased alanine demand. Cells lacking SLC38A2 fail to concentrate intracellular alanine and undergo a profound metabolic crisis resulting in markedly impaired tumor growth. Our results demonstrate that stromal–cancer metabolic niches can form through differential transporter expression, creating unique therapeutic opportunities to target metabolic demands of cancer.
Significance:
This work identifies critical neutral amino acid transporters involved in channeling alanine between pancreatic stellate and PDAC cells. Targeting PDAC-specific alanine uptake results in a metabolic crisis impairing metabolism, proliferation, and tumor growth. PDAC cells specifically activate and require SLC38A2 to fuel their alanine demands that may be exploited therapeutically.

This article is highlighted in the In This Issue feature, p. 890
Data from Disabled Homolog 2 Controls Prometastatic Activity of Tumor-Associated Macrophages
Authors: Marigo Ilaria , Trovato Rosalinda , Hofer Francesca , Ingangi Vincenzo , De Sanctis Francesco , Ugel Stefano , Canè Stefania , Simonelli Anna , Lamolinara Alessia , Iezzi Manuela , Fassan Matteo , Rugge Massimo , Boschi Federico , Borile Giulia , Eisenhaure Thomas , Sarkizova Siranush , Lieb David , Hacohen Nir , Azzolin Luca , Piccolo Stefano , Lawlor Rita , Scarpa Aldo , Carbognin Luisa , Bria Emilio , Bicciato Silvio , Murray Peter J. , Bronte Vincenzo
Published: April 2023

Abstract
Tumor-associated macrophages (TAM) are regulators of extracellular matrix (ECM) remodeling and metastatic progression, the main cause of cancer-associated death. We found that disabled homolog 2 mitogen-responsive phosphoprotein (DAB2) is highly expressed in tumor-infiltrating TAMs and that its genetic ablation significantly impairs lung metastasis formation. DAB2-expressing TAMs, mainly localized along the tumor-invasive front, participate in integrin recycling, ECM remodeling, and directional migration in a tridimensional matrix. DAB2+ macrophages escort the invasive dissemination of cancer cells by a mechanosensing pathway requiring the transcription factor YAP. In human lobular breast and gastric carcinomas, DAB2+ TAMs correlated with a poor clinical outcome, identifying DAB2 as potential prognostic biomarker for stratification of patients with cancer. DAB2 is therefore central for the prometastatic activity of TAMs.
Significance:
DAB2 expression in macrophages is essential for metastasis formation but not primary tumor growth. Mechanosensing cues, activating the complex YAP–TAZ, regulate DAB2 in macrophages, which in turn controls integrin recycling and ECM remodeling in 3-D tissue matrix. The presence of DAB2+ TAMs in patients with cancer correlates with worse prognosis.

This article is highlighted in the In This Issue feature, p. 1611
Data from BI-3406, a Potent and Selective SOS1–KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition
Authors: Hofmann Marco H. , Gmachl Michael , Ramharter Juergen , Savarese Fabio , Gerlach Daniel , Marszalek Joseph R. , Sanderson Michael P. , Kessler Dirk , Trapani Francesca , Arnhof Heribert , Rumpel Klaus , Botesteanu Dana-Adriana , Ettmayer Peter , Gerstberger Thomas , Kofink Christiane , Wunberg Tobias , Zoephel Andreas , Fu Szu-Chin , Teh Jessica L. , Böttcher Jark , Pototschnig Nikolai , Schachinger Franziska , Schipany Katharina , Lieb Simone , Vellano Christopher P. , O'Connell Jonathan C. , Mendes Rachel L. , Moll Jurgen , Petronczki Mark , Heffernan Timothy P. , Pearson Mark , McConnell Darryl B. , Kraut Norbert
Published: April 2023

Abstract
KRAS is the most frequently mutated driver of pancreatic, colorectal, and non–small cell lung cancers. Direct KRAS blockade has proved challenging, and inhibition of a key downstream effector pathway, the RAF–MEK–ERK cascade, has shown limited success because of activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective, and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1, thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors.
Significance:
To date, there are no effective targeted pan-KRAS therapies. In-depth characterization of BI-3406 activity and identification of MEK inhibitors as effective combination partners provide an attractive therapeutic concept for the majority of KRAS-mutant cancers, including those fueled by the most prevalent mutant KRAS oncoproteins, G12D, G12V, G12C, and G13D.

See related commentary by Zhao et al., p. 17.

This article is highlighted in the In This Issue feature, p. 1
Data from An In Vivo Kras Allelic Series Reveals Distinct Phenotypes of Common Oncogenic Variants
Authors: Zafra Maria Paz , Parsons Marie J. , Kim Jangkyung , Alonso-Curbelo Direna , Goswami Sukanya , Schatoff Emma M. , Han Teng , Katti Alyna , Fernandez Maria Teresa Calvo , Wilkinson John E. , Piskounova Elena , Dow Lukas E.
Published: April 2023

Abstract
KRAS is the most frequently mutated oncogene in cancer, yet there is little understanding of how specific KRAS amino acid changes affect tumor initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRASG12C), pancreas (KRASG12R), and colon (KRASG13D) cancers. Induction of each allele in either the murine colon or pancreas revealed striking quantitative and qualitative differences between KRAS mutants in driving the early stages of transformation. Furthermore, using pancreatic organoid models, we show that KRASG13D mutants are sensitive to EGFR inhibition, whereas KRASG12C-mutant organoids are selectively responsive to covalent G12C inhibitors only when EGFR is suppressed. Together, these new mouse strains provide an ideal platform for investigating KRAS biology in vivo and for developing preclinical precision oncology models of KRAS-mutant pancreas, colon, and lung cancers.
Significance:
KRAS is the most frequently mutated oncogene. Here, we describe new preclinical models that mimic tissue-selective KRAS mutations and show that each mutation has distinct cellular consequences in vivo and carries differential sensitivity to targeted therapeutic agents.

See related commentary by Kostyrko and Sweet-Cordero, p. 1626.

This article is highlighted in the In This Issue feature, p. 1611
Data from Myeloid-Derived Suppressor Cell Subsets Drive Glioblastoma Growth in a Sex-Specific Manner
Authors: Bayik Defne , Zhou Yadi , Park Chihyun , Hong Changjin , Vail Daniel , Silver Daniel J. , Lauko Adam , Roversi Gustavo , Watson Dionysios C. , Lo Alice , Alban Tyler J. , McGraw Mary , Sorensen Mia , Grabowski Matthew M. , Otvos Balint , Vogelbaum Michael A. , Horbinski Craig , Kristensen Bjarne Winther , Khalil Ahmad M. , Hwang Tae Hyun , Ahluwalia Manmeet S. , Cheng Feixiong , Lathia Justin D.
Published: April 2023

Abstract
Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct contributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network medicine analysis, we demonstrated in preclinical models that mMDSCs could be targeted with antiproliferative agents in males, whereas gMDSC function could be inhibited by IL1β blockade in females. Analysis of patient data confirmed that proliferating mMDSCs were predominant in male tumors and that a high gMDSC/IL1β gene signature correlated with poor prognosis in female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM.
Significance:
Sexual dimorphism at the level of MDSC subset prevalence, localization, and gene-expression profile constitutes a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSCs in males, whereas IL1 pathway inhibitors can provide benefit to females via inhibition of gMDSCs.

See related commentary by Gabrilovich et al., p. 1100.

This article is highlighted in the In This Issue feature, p. 1079
Data from Priority COVID-19 Vaccination for Patients with Cancer while Vaccine Supply Is Limited
Authors: Ribas Antoni , Sengupta Rajarshi , Locke Trevan , Zaidi Sayyed Kaleem , Campbell Katie M. , Carethers John M. , Jaffee Elizabeth M. , Wherry E. John , Soria Jean-Charles , D'Souza Gypsyamber
Published: April 2023

AbstractSummary:
Published series on COVID-19 support the notion that patients with cancer are a particularly vulnerable population. There is a confluence of risk factors between cancer and COVID-19, and cancer care and treatments increase exposure to the virus and may dampen natural immune responses. The available evidence supports the conclusion that patients with cancer, in particular with hematologic malignancies, should be considered among the very high-risk groups for priority COVID-19 vaccination.
Data from Tumor Microenvironment Is Critical for the Maintenance of Cellular States Found in Primary Glioblastomas
Authors: Pine Allison R. , Cirigliano Stefano M. , Nicholson James G. , Hu Yang , Linkous Amanda , Miyaguchi Ken , Edwards Lincoln , Singhania Richa , Schwartz Theodore H. , Ramakrishna Rohan , Pisapia David J. , Snuderl Matija , Elemento Olivier , Fine Howard A.
Published: April 2023

Abstract
Glioblastoma (GBM), an incurable tumor, remains difficult to model and more importantly to treat due to its genetic/epigenetic heterogeneity and plasticity across cellular states. The ability of current tumor models to recapitulate the cellular states found in primary tumors remains unexplored. To address this issue, we compared single-cell RNA sequencing of tumor cells from 5 patients across four patient-specific glioblastoma stem cell (GSC)–derived model types, including glioma spheres, tumor organoids, glioblastoma cerebral organoids (GLICO), and patient-derived xenografts. We find that GSCs within the GLICO model are enriched for a neural progenitor–like cell subpopulation and recapitulate the cellular states and their plasticity found in the corresponding primary parental tumors. These data demonstrate how the contribution of a neuroanatomically accurate human microenvironment is critical and sufficient for recapitulating the cellular states found in human primary GBMs, a principle that may likely apply to other tumor models.
Significance:
It has been unclear how well different patient-derived GBM models are able to recreate the full heterogeneity of primary tumors. Here, we provide a complete transcriptomic characterization of the major model types. We show that the microenvironment is crucial for recapitulating GSC cellular states, highlighting the importance of tumor–host cell interactions.

See related commentary by Luo and Weiss, p. 907.

This article is highlighted in the In This Issue feature, p. 890
Data from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer
Authors: Wander Seth A. , Cohen Ofir , Gong Xueqian , Johnson Gabriela N. , Buendia-Buendia Jorge E. , Lloyd Maxwell R. , Kim Dewey , Luo Flora , Mao Pingping , Helvie Karla , Kowalski Kailey J. , Nayar Utthara , Waks Adrienne G. , Parsons Stephen H. , Martinez Ricardo , Litchfield Lacey M. , Ye Xiang S. , Yu Chunping , Jansen Valerie M. , Stille John R. , Smith Patricia S. , Oakley Gerard J. , Chu Quincy S. , Batist Gerald , Hughes Melissa E. , Kremer Jill D. , Garraway Levi A. , Winer Eric P. , Tolaney Sara M. , Lin Nancy U. , Buchanan Sean G. , Wagle Nikhil
Published: April 2023

Abstract
Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor–positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations—in AKT1, RAS, and AURKA—have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients.
Significance:
We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.

This article is highlighted in the In This Issue feature, p. 1079
Data from Poly(ADP-ribose) Glycohydrolase Inhibition Sequesters NAD+ to Potentiate the Metabolic Lethality of Alkylating Chemotherapy in IDH-Mutant Tumor Cells
Authors: Nagashima Hiroaki , Lee Christine K. , Tateishi Kensuke , Higuchi Fumi , Subramanian Megha , Rafferty Seamus , Melamed Lisa , Miller Julie J. , Wakimoto Hiroaki , Cahill Daniel P.
Published: April 2023

Abstract
NAD+ is an essential cofactor metabolite and is the currency of metabolic transactions critical for cell survival. Depending on tissue context and genotype, cancer cells have unique dependencies on NAD+ metabolic pathways. PARPs catalyze oligomerization of NAD+ monomers into PAR chains during cellular response to alkylating chemotherapeutics, including procarbazine or temozolomide. Here we find that, in endogenous IDH1-mutant tumor models, alkylator-induced cytotoxicity is markedly augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme PAR glycohydrolase (PARG). Both in vitro and in vivo, we observe that concurrent alkylator and PARG inhibition depletes freely available NAD+ by preventing PAR breakdown, resulting in NAD+ sequestration and collapse of metabolic homeostasis. This effect reversed with NAD+ rescue supplementation, confirming the mechanistic basis of cytotoxicity. Thus, alkylating chemotherapy exposes a genotype-specific metabolic weakness in tumor cells that can be exploited by PARG inactivation.
Significance:
Oncogenic mutations in the isocitrate dehydrogenase genes IDH1 or IDH2 initiate diffuse gliomas of younger adulthood. Strategies to maximize the effectiveness of chemotherapy in these tumors are needed. We discover alkylating chemotherapy and concurrent PARG inhibition exploits an intrinsic metabolic weakness within these cancer cells to provide genotype-specific benefit.

See related commentary by Pirozzi and Yan, p. 1629.

This article is highlighted in the In This Issue feature, p. 1611
Data from Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction
Authors: Singh Nathan , Lee Yong Gu , Shestova Olga , Ravikumar Pranali , Hayer Katharina E. , Hong Seok Jae , Lu Xueqing Maggie , Pajarillo Raymone , Agarwal Sangya , Kuramitsu Shunichiro , Orlando Elena J. , Mueller Karen Thudium , Good Charly R. , Berger Shelley L. , Shalem Ophir , Weitzman Matthew D. , Frey Noelle V. , Maude Shannon L. , Grupp Stephan A. , June Carl H. , Gill Saar , Ruella Marco
Published: April 2023

Abstract
Primary resistance to CD19-directed chimeric antigen receptor T-cell therapy (CART19) occurs in 10% to 20% of patients with acute lymphoblastic leukemia (ALL); however, the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T-cell cytotoxicity that permitted antigen persistence and was subsequently magnified by the induction of CAR T-cell functional impairment. These findings were validated using samples from two CAR T-cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T-cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T-cell failure by impairing T-cell cytotoxicity and promoting progressive CAR T-cell dysfunction.
Significance:
Resistance to CART19 is a significant barrier to efficacy in the treatment of B-cell malignancies. This work demonstrates that impaired death receptor signaling in tumor cells causes failed CART19 cytotoxicity and drives CART19 dysfunction, identifying a novel mechanism of antigen-independent resistance to CAR therapy.

See related commentary by Green and Neelapu, p. 492.
Data from Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia
Authors: Pei Shanshan , Pollyea Daniel A. , Gustafson Annika , Stevens Brett M. , Minhajuddin Mohammad , Fu Rui , Riemondy Kent A. , Gillen Austin E. , Sheridan Ryan M. , Kim Jihye , Costello James C. , Amaya Maria L. , Inguva Anagha , Winters Amanda , Ye Haobin , Krug Anna , Jones Courtney L. , Adane Biniam , Khan Nabilah , Ponder Jessica , Schowinsky Jeffrey , Abbott Diana , Hammes Andrew , Myers Jason R. , Ashton John M. , Nemkov Travis , D'Alessandro Angelo , Gutman Jonathan A. , Ramsey Haley E. , Savona Michael R. , Smith Clayton A. , Jordan Craig T.
Published: April 2023

Abstract
Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated patients with acute myeloid leukemia (AML). However, up-front resistance as well as relapse following initial response demonstrates the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax +azacitidine in patients with AML correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptomic profile, loses expression of venetoclax target BCL2, and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis.
Significance:
Identifying characteristics of patients who respond poorly to venetoclax-based therapy and devising alternative therapeutic strategies for such patients are important topics in AML. We show that venetoclax resistance can arise due to intrinsic molecular/metabolic properties of monocytic AML cells and that such properties can potentially be targeted with alternative strategies.
Data from The KRASG12C Inhibitor MRTX849 Provides Insight toward Therapeutic Susceptibility of KRAS-Mutant Cancers in Mouse Models and Patients
Authors: Hallin Jill , Engstrom Lars D. , Hargis Lauren , Calinisan Andrew , Aranda Ruth , Briere David M. , Sudhakar Niranjan , Bowcut Vickie , Baer Brian R. , Ballard Joshua A. , Burkard Michael R. , Fell Jay B. , Fischer John P. , Vigers Guy P. , Xue Yaohua , Gatto Sole , Fernandez-Banet Julio , Pavlicek Adam , Velastagui Karen , Chao Richard C. , Barton Jeremy , Pierobon Mariaelena , Baldelli Elisa , Patricoin Emanuel F. , Cassidy Douglas P. , Marx Matthew A. , Rybkin Igor I. , Johnson Melissa L. , Ou Sai-Hong Ignatius , Lito Piro , Papadopoulos Kyriakos P. , Jänne Pasi A. , Olson Peter , Christensen James G.
Published: April 2023

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

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

This article is highlighted in the In This Issue feature, p. 1
Data from Mutant BRAF and MEK Inhibitors Regulate the Tumor Immune Microenvironment via Pyroptosis
Authors: Erkes Dan A. , Cai Weijia , Sanchez Ileine M. , Purwin Timothy J. , Rogers Corey , Field Conroy O. , Berger Adam C. , Hartsough Edward J. , Rodeck Ulrich , Alnemri Emad S. , Aplin Andrew E.
Published: April 2023

Abstract
Combinations of BRAF inhibitors and MEK inhibitors (BRAFi + MEKi) are FDA-approved to treat BRAFV600E/K-mutant melanoma. Efficacy of BRAFi + MEKi associates with cancer cell death and alterations in the tumor immune microenvironment; however, the links are poorly understood. We show that BRAFi + MEKi caused durable melanoma regression in an immune-mediated manner. BRAFi + MEKi treatment promoted cleavage of gasdermin E (GSDME) and release of HMGB1, markers of pyroptotic cell death. GSDME-deficient melanoma showed defective HMGB1 release, reduced tumor-associated T cell and activated dendritic cell infiltrates in response to BRAFi + MEKi, and more frequent tumor regrowth after drug removal. Importantly, BRAFi + MEKi–resistant disease lacked pyroptosis markers and showed decreased intratumoral T-cell infiltration but was sensitive to pyroptosis-inducing chemotherapy. These data implicate BRAFi + MEKi–induced pyroptosis in antitumor immune responses and highlight new therapeutic strategies for resistant melanoma.
Significance:
Targeted inhibitors and immune checkpoint agents have advanced the care of patients with melanoma; however, detailed knowledge of the intersection between these two research areas is lacking. We describe a molecular mechanism of targeted inhibitor regulation of an immune-stimulatory form of cell death and provide a proof-of-principle salvage therapy concept for inhibitor-resistant melanoma.

See related commentary by Smalley, p. 176.

This article is highlighted in the In This Issue feature, p. 161