bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer
Authors: Dienstmann Rodrigo , Patnaik Amita , Garcia-Carbonero Rocio , Cervantes Andrés , Benavent Marta , Roselló Susana , Tops Bastiaan B.J. , van der Post Rachel S. , Argilés Guillem , Skartved Niels J.Ø. , Hansen Ulla H. , Hald Rikke , Pedersen Mikkel W. , Kragh Michael , Horak Ivan D. , Braun Stephan , Van Cutsem Eric , Tolcher Anthony W. , Tabernero Josep
Published: April 2023

Abstract
Tumor growth in the context of EGFR inhibitor resistance may remain EGFR-dependent and is mediated by mechanisms including compensatory ligand upregulation and de novo gene alterations. Sym004 is a two-antibody mixture targeting nonoverlapping EGFR epitopes. In preclinical models, Sym004 causes significant EGFR internalization and degradation, which translates into superior growth inhibition in the presence of ligands. In this phase I trial, we observed grade 3 skin toxicity and hypomagnesemia as mechanism-based dose-limiting events during dose escalation. In dose-expansion cohorts of 9 and 12 mg/kg of Sym004 weekly, patients with metastatic colorectal cancer and acquired EGFR inhibitor resistance were enrolled; 17 of 39 patients (44%) had tumor shrinkage, with 5 patients (13%) achieving partial response. Pharmacodynamic studies confirmed marked Sym004-induced EGFR downmodulation. MET gene amplification emerged in 1 patient during Sym004 treatment, and a partial response was seen in a patient with EGFRS492R mutation that is predictive of cetuximab resistance.

Significance: Potent EGFR downmodulation with Sym004 in patients with metastatic colorectal cancer and acquired resistance to cetuximab/panitumumab translates into significant antitumor activity and validates the preclinical hypothesis that a proportion of tumors remains dependent on EGFR signaling. Further clinical development and expanded correlative analyses of response patterns with secondary RAS/EGFR mutations are warranted. Cancer Discov; 5(6);598–609. ©2015 AACR.

See related commentary by Stintzing and Heinemann, p. 578

This article is highlighted in the In This Issue feature, p. 565
Data from Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma
Authors: Rajbhandari Presha , Lopez Gonzalo , Capdevila Claudia , Salvatori Beatrice , Yu Jiyang , Rodriguez-Barrueco Ruth , Martinez Daniel , Yarmarkovich Mark , Weichert-Leahey Nina , Abraham Brian J. , Alvarez Mariano J. , Iyer Archana , Harenza Jo Lynne , Oldridge Derek , De Preter Katleen , Koster Jan , Asgharzadeh Shahab , Seeger Robert C. , Wei Jun S. , Khan Javed , Vandesompele Jo , Mestdagh Pieter , Versteeg Rogier , Look A. Thomas , Young Richard A. , Iavarone Antonio , Lasorella Anna , Silva Jose M. , Maris John M. , Califano Andrea
Published: April 2023

Abstract
High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator proteins that were conserved across independent cohorts. A 10-protein transcriptional module—centered around a TEAD4–MYCN positive feedback loop—emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo. Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional coactivators YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN-deregulated neuroblastomas.

Significance: Despite progress in understanding of neuroblastoma genetics, little progress has been made toward personalized treatment. Here, we present a framework to determine the downstream effectors of the genetic alterations sustaining neuroblastoma subtypes, which can be easily extended to other tumor types. We show the critical effect of disrupting a 10-protein module centered around a YAP/TAZ-independent TEAD4–MYCN positive feedback loop in MYCNAmp neuroblastomas, nominating TEAD4 as a novel candidate for therapeutic intervention. Cancer Discov; 8(5); 582–99. ©2018 AACR.

This article is highlighted in the In This Issue feature, p. 517
Data from Spatiotemporal Loss of NF1 in Schwann Cell Lineage Leads to Different Types of Cutaneous Neurofibroma Susceptible to Modification by the Hippo Pathway
Authors: Chen Zhiguo , Mo Juan , Brosseau Jean-Philippe , Shipman Tracey , Wang Yong , Liao Chung-Ping , Cooper Jonathan M. , Allaway Robert J. , Gosline Sara J.C. , Guinney Justin , Carroll Thomas J. , Le Lu Q.
Published: April 2023

Abstract
Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor suppressor neurofibromin, a negative regulator of RAS signaling. Patients with NF1 present with a wide range of clinical manifestations, and the tumor with highest prevalence is cutaneous neurofibroma (cNF). Most patients harboring cNF suffer greatly from the burden of those tumors, which have no effective medical treatment. Ironically, none of the numerous NF1 mouse models developed so far recapitulate cNF. Here, we discovered that HOXB7 serves as a lineage marker to trace the developmental origin of cNF neoplastic cells. Ablating Nf1 in the HOXB7 lineage faithfully recapitulates both human cutaneous and plexiform neurofibroma. In addition, we discovered that modulation of the Hippo pathway acts as a “modifier” for neurofibroma tumorigenesis. This mouse model opens the doors for deciphering the evolution of cNF to identify effective therapies, where none exist today.
Significance:
This study provides insights into the developmental origin of cNF, the most common tumor in NF1, and generates the first mouse model that faithfully recapitulates both human cutaneous and plexiform neurofibroma. The study also demonstrates that the Hippo pathway can modify neurofibromagenesis, suggesting that dampening the Hippo pathway could be an attractive therapeutic target.

This article is highlighted in the In This Issue feature, p. 1
Data from nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer
Authors: Frese Kristopher K. , Neesse Albrecht , Cook Natalie , Bapiro Tashinga E. , Lolkema Martijn P. , Jodrell Duncan I. , Tuveson David A.
Published: April 2023

Abstract
Nanoparticle albumin-bound (nab)-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). The limited availability of patient tissue and exquisite sensitivity of xenografts to chemotherapeutics have limited our ability to address the mechanistic basis of this treatment regimen. Here, we used a mouse model of PDA to show that the coadministration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Combination treatment increases intratumoral gemcitabine levels attributable to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase. Correspondingly, paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species–mediated degradation, resulting in the increased stabilization of gemcitabine. Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials.

Significance: This study provides mechanistic insight into the clinical cooperation observed between gemcitabine and nab-paclitaxel in the treatment of pancreatic cancer. Cancer Discovery; 2(3); 260–9. ©2012 AACR.

Read the Commentary on this article by Clark, p. 208

This article is highlighted in the In This Issue feature, p. 193
Data from Phf6 Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL
Authors: Wendorff Agnieszka A. , Quinn S. Aidan , Rashkovan Marissa , Madubata Chioma J. , Ambesi-Impiombato Alberto , Litzow Mark R. , Tallman Martin S. , Paietta Elisabeth , Paganin Maddalena , Basso Giuseppe , Gastier-Foster Julie M. , Loh Mignon L. , Rabadan Raul , Van Vlierberghe Pieter , Ferrando Adolfo A.
Published: April 2023

Abstract
The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL.
Significance:
Phf6 controls HSC homeostasis, leukemia initiation, and T-ALL leukemia-initiating cell self-renewal. These results substantiate a role for PHF6 mutations as early events and drivers of leukemia stem cell activity in the pathogenesis of T-ALL.

This article is highlighted in the In This Issue feature, p. 305
Data from Allele-Specific Mechanisms of Activation of MEK1 Mutants Determine Their Properties
Authors: Gao Yijun , Chang Matthew T. , McKay Daniel , Na Na , Zhou Bing , Yaeger Rona , Torres Neilawattie M. , Muniz Keven , Drosten Matthias , Barbacid Mariano , Caponigro Giordano , Stuart Darrin , Moebitz Henrik , Solit David B. , Abdel-Wahab Omar , Taylor Barry S. , Yao Zhan , Rosen Neal
Published: April 2023

Abstract
Mutations at multiple sites in MEK1 occur in cancer, suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS/RAF-dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output, and often cooccur with RAS or RAF mutations. They act as amplifiers of RAF signaling. In contrast, another class of mutants deletes a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, is unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity. Moreover, these RAF-independent mutants are insensitive to allosteric MEK inhibitors, which preferentially bind to the inactivated form of MEK1. All the mutants are sensitive to an ATP-competitive MEK inhibitor. Thus, our study comprises a novel therapeutic strategy for tumors driven by RAF-independent MEK1 mutants.

Significance: Mutants with which MEK1 mutants coexist and their sensitivity to inhibitors are determined by allele-specific properties. This study shows the importance of functional characterization of mutant alleles in single oncogenes and identifies a new class of MEK1 mutants, insensitive to current MEK1 inhibitors but treatable with a new ATP-competitive inhibitor. Cancer Discov; 8(5); 648–61. ©2018 AACR.

See related commentary by Maust et al., p. 534.

This article is highlighted in the In This Issue feature, p. 517
Data from Isoform Switching as a Mechanism of Acquired Resistance to Mutant Isocitrate Dehydrogenase Inhibition
Authors: Harding James J. , Lowery Maeve A. , Shih Alan H. , Schvartzman Juan M. , Hou Shengqi , Famulare Christopher , Patel Minal , Roshal Mikhail , Do Richard K. , Zehir Ahmet , You Daoqi , Selcuklu S. Duygu , Viale Agnes , Tallman Martin S. , Hyman David M. , Reznik Ed , Finley Lydia W.S. , Papaemmanuil Elli , Tosolini Alessandra , Frattini Mark G. , MacBeth Kyle J. , Liu Guowen , Fan Bin , Choe Sung , Wu Bin , Janjigian Yelena Y. , Mellinghoff Ingo K. , Diaz Luis A. , Levine Ross L. , Abou-Alfa Ghassan K. , Stein Eytan M. , Intlekofer Andrew M.
Published: April 2023

Abstract
Somatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors.
Significance:
IDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by “isoform switching” from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2HG production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.

This article is highlighted in the In This Issue feature, p. 1494
Data from Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma
Authors: Hong Aayoung , Moriceau Gatien , Sun Lu , Lomeli Shirley , Piva Marco , Damoiseaux Robert , Holmen Sheri L. , Sharpless Norman E. , Hugo Willy , Lo Roger S.
Published: April 2023

Abstract
Melanoma resistant to MAPK inhibitors (MAPKi) displays loss of fitness upon experimental MAPKi withdrawal and, clinically, may be resensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi addiction in MAPKi-resistant BRAFMUT or NRASMUT melanoma. MAPKi-addiction phenotypes evident upon drug withdrawal spanned transient cell-cycle slowdown to cell-death responses, the latter of which required a robust phosphorylated ERK (pERK) rebound. Generally, drug withdrawal–induced pERK rebound upregulated p38–FRA1–JUNB–CDKN1A and downregulated proliferation, but only a robust pERK rebound resulted in DNA damage and parthanatos-related cell death. Importantly, pharmacologically impairing DNA damage repair during MAPKi withdrawal augmented MAPKi addiction across the board by converting a cell-cycle deceleration to a caspase-dependent cell-death response or by furthering parthanatos-related cell death. Specifically in MEKi-resistant NRASMUT or atypical BRAFMUT melanoma, treatment with a type I RAF inhibitor intensified pERK rebound elicited by MEKi withdrawal, thereby promoting a cell death–predominant MAPKi-addiction phenotype. Thus, MAPKi discontinuation upon disease progression should be coupled with specific strategies that augment MAPKi addiction.

Significance: Discontinuing targeted therapy may select against drug-resistant tumor clones, but drug-addiction mechanisms are ill-defined. Using melanoma resistant to but withdrawn from MAPKi, we defined a synthetic lethality between supraphysiologic levels of pERK and DNA damage. Actively promoting this synthetic lethality could rationalize sequential/rotational regimens that address evolving vulnerabilities. Cancer Discov; 8(1); 74–93. ©2017 AACR.

See related commentary by Stern, p. 20.

This article is highlighted in the In This Issue feature, p. 1
Data from A Novel MCL1 Inhibitor Combined with Venetoclax Rescues Venetoclax-Resistant Acute Myelogenous Leukemia
Authors: Ramsey Haley E. , Fischer Melissa A. , Lee Taekyu , Gorska Agnieszka E. , Arrate Maria Pia , Fuller Londa , Boyd Kelli L. , Strickland Stephen A. , Sensintaffar John , Hogdal Leah J. , Ayers Gregory D. , Olejniczak Edward T. , Fesik Stephen W. , Savona Michael R.
Published: April 2023

Abstract
Suppression of apoptosis by expression of antiapoptotic BCL2 family members is a hallmark of acute myeloblastic leukemia (AML). Induced myeloid leukemia cell differentiation protein (MCL1), an antiapoptotic BCL2 family member, is commonly upregulated in AML cells and is often a primary mode of resistance to treatment with the BCL2 inhibitor venetoclax. Here, we describe VU661013, a novel, potent, selective MCL1 inhibitor that destabilizes BIM/MCL1 association, leads to apoptosis in AML, and is active in venetoclax-resistant cells and patient-derived xenografts. In addition, VU661013 was safely combined with venetoclax for synergy in murine models of AML. Importantly, BH3 profiling of patient samples and drug-sensitivity testing ex vivo accurately predicted cellular responses to selective inhibitors of MCL1 or BCL2 and showed benefit of the combination. Taken together, these data suggest a strategy of rationally using BCL2 and MCL1 inhibitors in sequence or in combination in AML clinical trials.
Significance:
Targeting antiapoptotic proteins in AML is a key therapeutic strategy, and MCL1 is a critical antiapoptotic oncoprotein. Armed with novel MCL1 inhibitors and the potent BCL2 inhibitor venetoclax, it may be possible to selectively induce apoptosis by combining or thoughtfully sequencing these inhibitors based on a rational evaluation of AML.

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

This article is highlighted in the In This Issue feature, p. 1494
Data from Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma
Authors: Pectasides Eirini , Stachler Matthew D. , Derks Sarah , Liu Yang , Maron Steven , Islam Mirazul , Alpert Lindsay , Kwak Heewon , Kindler Hedy , Polite Blase , Sharma Manish R. , Allen Kenisha , O'Day Emily , Lomnicki Samantha , Maranto Melissa , Kanteti Rajani , Fitzpatrick Carrie , Weber Christopher , Setia Namrata , Xiao Shu-Yuan , Hart John , Nagy Rebecca J. , Kim Kyoung-Mee , Choi Min-Gew , Min Byung-Hoon , Nason Katie S. , O'Keefe Lea , Watanabe Masayuki , Baba Hideo , Lanman Rick , Agoston Agoston T. , Oh David J. , Dunford Andrew , Thorner Aaron R. , Ducar Matthew D. , Wollison Bruce M. , Coleman Haley A. , Ji Yuan , Posner Mitchell C. , Roggin Kevin , Turaga Kiran , Chang Paul , Hogarth Kyle , Siddiqui Uzma , Gelrud Andres , Ha Gavin , Freeman Samuel S. , Rhoades Justin , Reed Sarah , Gydush Greg , Rotem Denisse , Davison Jon , Imamura Yu , Adalsteinsson Viktor , Lee Jeeyun , Bass Adam J. , Catenacci Daniel V.
Published: April 2023

Abstract
Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy.

Significance: We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated. Cancer Discov; 8(1); 37–48. ©2017 AACR.

See related commentary by Sundar and Tan, p. 14.

See related article by Janjigian et al., p. 49.

This article is highlighted in the In This Issue feature, p. 1
Data from Landscape of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion
Authors: Piotrowska Zofia , Isozaki Hideko , Lennerz Jochen K. , Gainor Justin F. , Lennes Inga T. , Zhu Viola W. , Marcoux Nicolas , Banwait Mandeep K. , Digumarthy Subba R. , Su Wenjia , Yoda Satoshi , Riley Amanda K. , Nangia Varuna , Lin Jessica J. , Nagy Rebecca J. , Lanman Richard B. , Dias-Santagata Dora , Mino-Kenudson Mari , Iafrate A. John , Heist Rebecca S. , Shaw Alice T. , Evans Erica K. , Clifford Corinne , Ou Sai-Hong I. , Wolf Beni , Hata Aaron N. , Sequist Lecia V.
Published: April 2023

Abstract
We present a cohort of 41 patients with osimertinib resistance biopsies, including 2 with an acquired CCDC6–RET fusion. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their role in acquired resistance to EGFR inhibitors is not well described. To assess the biological implications of RET fusions in an EGFR-mutant cancer, we expressed CCDC6–RET in PC9 (EGFR del19) and MGH134 (EGFR L858R/T790M) cells and found that CCDC6–RET was sufficient to confer resistance to EGFR tyrosine kinase inhibitors (TKI). The selective RET inhibitors BLU-667 and cabozantinib resensitized CCDC6–RET-expressing cells to EGFR inhibition. Finally, we treated 2 patients with EGFR-mutant NSCLC and RET-mediated resistance with osimertinib and BLU-667. The combination was well tolerated and led to rapid radiographic response in both patients. This study provides proof of concept that RET fusions can mediate acquired resistance to EGFR TKIs and that combined EGFR and RET inhibition with osimertinib/BLU-667 may be a well-tolerated and effective treatment strategy for such patients.
Significance:
The role of RET fusions in resistant EGFR-mutant cancers is unknown. We report that RET fusions mediate resistance to EGFR inhibitors and demonstrate that this bypass track can be effectively targeted with a selective RET inhibitor (BLU-667) in the clinic.

This article is highlighted in the In This Issue feature, p. 1494
Data from MYC Instructs and Maintains Pancreatic Adenocarcinoma Phenotype
Authors: Sodir Nicole M. , Kortlever Roderik M. , Barthet Valentin J.A. , Campos Tania , Pellegrinet Luca , Kupczak Steven , Anastasiou Panayiotis , Swigart Lamorna Brown , Soucek Laura , Arends Mark J. , Littlewood Trevor D. , Evan Gerard I.
Published: April 2023

Abstract
The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of Myc in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells in vivo is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this Myc-driven PDAC switch is completely and immediately reversible: Myc deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible Myc switch.
Significance:
We show that Myc activation in indolent KrasG12D-induced PanIN epithelium acts as an immediate pleiotropic switch, triggering tissue-specific signals that instruct all the diverse signature stromal features of spontaneous human PDAC. Subsequent Myc deactivation or inhibition immediately triggers a program that coordinately disassembles PDAC back to PanIN.

See related commentary by English and Sears, p. 495.
Data from Lower Airway Dysbiosis Affects Lung Cancer Progression
Authors: Tsay Jun-Chieh J. , Wu Benjamin G. , Sulaiman Imran , Gershner Katherine , Schluger Rosemary , Li Yonghua , Yie Ting-An , Meyn Peter , Olsen Evan , Perez Luisannay , Franca Brendan , Carpenito Joseph , Iizumi Tadasu , El-Ashmawy Mariam , Badri Michelle , Morton James T. , Shen Nan , He Linchen , Michaud Gaetane , Rafeq Samaan , Bessich Jamie L. , Smith Robert L. , Sauthoff Harald , Felner Kevin , Pillai Ray , Zavitsanou Anastasia-Maria , Koralov Sergei B. , Mezzano Valeria , Loomis Cynthia A. , Moreira Andre L. , Moore William , Tsirigos Aristotelis , Heguy Adriana , Rom William N. , Sterman Daniel H. , Pass Harvey I. , Clemente Jose C. , Li Huilin , Bonneau Richard , Wong Kwok-Kin , Papagiannakopoulos Thales , Segal Leopoldo N.
Published: April 2023

Abstract
In lung cancer, enrichment of the lower airway microbiota with oral commensals commonly occurs, and ex vivo models support that some of these bacteria can trigger host transcriptomic signatures associated with carcinogenesis. Here, we show that this lower airway dysbiotic signature was more prevalent in the stage IIIB–IV tumor–node–metastasis lung cancer group and is associated with poor prognosis, as shown by decreased survival among subjects with early-stage disease (I–IIIA) and worse tumor progression as measured by RECIST scores among subjects with stage IIIB–IV disease. In addition, this lower airway microbiota signature was associated with upregulation of the IL17, PI3K, MAPK, and ERK pathways in airway transcriptome, and we identified Veillonella parvula as the most abundant taxon driving this association. In a KP lung cancer model, lower airway dysbiosis with V. parvula led to decreased survival, increased tumor burden, IL17 inflammatory phenotype, and activation of checkpoint inhibitor markers.
Significance:
Multiple lines of investigation have shown that the gut microbiota affects host immune response to immunotherapy in cancer. Here, we support that the local airway microbiota modulates the host immune tone in lung cancer, affecting tumor progression and prognosis.

See related commentary by Zitvogel and Kroemer, p. 224.

This article is highlighted in the In This Issue feature, p. 211
Data from Relapse-Fated Latent Diagnosis Subclones in Acute B Lineage Leukemia Are Drug Tolerant and Possess Distinct Metabolic Programs
Authors: Dobson Stephanie M. , García-Prat Laura , Vanner Robert J. , Wintersinger Jeffrey , Waanders Esmé , Gu Zhaohui , McLeod Jessica , Gan Olga I. , Grandal Ildiko , Payne-Turner Debbie , Edmonson Michael N. , Ma Xiaotu , Fan Yiping , Voisin Veronique , Chan-Seng-Yue Michelle , Xie Stephanie Z. , Hosseini Mohsen , Abelson Sagi , Gupta Pankaj , Rusch Michael , Shao Ying , Olsen Scott R. , Neale Geoffrey , Chan Steven M. , Bader Gary , Easton John , Guidos Cynthia J. , Danska Jayne S. , Zhang Jinghui , Minden Mark D. , Morris Quaid , Mullighan Charles G. , Dick John E.
Published: April 2023

Abstract
Disease recurrence causes significant mortality in B-progenitor acute lymphoblastic leukemia (B-ALL). Genomic analysis of matched diagnosis and relapse samples shows relapse often arising from minor diagnosis subclones. However, why therapy eradicates some subclones while others survive and progress to relapse remains obscure. Elucidation of mechanisms underlying these differing fates requires functional analysis of isolated subclones. Here, large-scale limiting dilution xenografting of diagnosis and relapse samples, combined with targeted sequencing, identified and isolated minor diagnosis subclones that initiate an evolutionary trajectory toward relapse [termed diagnosis Relapse Initiating clones (dRI)]. Compared with other diagnosis subclones, dRIs were drug-tolerant with distinct engraftment and metabolic properties. Transcriptionally, dRIs displayed enrichment for chromatin remodeling, mitochondrial metabolism, proteostasis programs, and an increase in stemness pathways. The isolation and characterization of dRI subclones reveals new avenues for eradicating dRI cells by targeting their distinct metabolic and transcriptional pathways before further evolution renders them fully therapy-resistant.
Significance:
Isolation and characterization of subclones from diagnosis samples of patients with B-ALL who relapsed showed that relapse-fated subclones had increased drug tolerance and distinct metabolic and survival transcriptional programs compared with other diagnosis subclones. This study provides strategies to identify and target clinically relevant subclones before further evolution toward relapse.

See related video: https://vimeo.com/442838617

See related article by E. Waanders et al.
Data from Circulating Tumor Cells Exhibit Metastatic Tropism and Reveal Brain Metastasis Drivers
Authors: Klotz Remi , Thomas Amal , Teng Teng , Han Sung Min , Iriondo Oihana , Li Lin , Restrepo-Vassalli Sara , Wang Alan , Izadian Negeen , MacKay Matthew , Moon Byoung-San , Liu Kevin J. , Ganesan Sathish Kumar , Lee Grace , Kang Diane S. , Walmsley Charlotte S. , Pinto Christopher , Press Michael F. , Lu Wange , Lu Janice , Juric Dejan , Bardia Aditya , Hicks James , Salhia Bodour , Attenello Frank , Smith Andrew D. , Yu Min
Published: April 2023

Abstract
Hematogenous metastasis is initiated by a subset of circulating tumor cells (CTC) shed from primary or metastatic tumors into the blood circulation. Thus, CTCs provide a unique patient biopsy resource to decipher the cellular subpopulations that initiate metastasis and their molecular properties. However, one crucial question is whether CTCs derived and expanded ex vivo from patients recapitulate human metastatic disease in an animal model. Here, we show that CTC lines established from patients with breast cancer are capable of generating metastases in mice with a pattern recapitulating most major organs from corresponding patients. Genome-wide sequencing analyses of metastatic variants identified semaphorin 4D as a regulator of tumor cell transmigration through the blood–brain barrier and MYC as a crucial regulator for the adaptation of disseminated tumor cells to the activated brain microenvironment. These data provide the direct experimental evidence of the promising role of CTCs as a prognostic factor for site-specific metastasis.
Significance:
Interests abound in gaining new knowledge of the physiopathology of brain metastasis. In a direct metastatic tropism analysis, we demonstrated that ex vivo–cultured CTCs from 4 patients with breast cancer showed organotropism, revealing molecular features that allow a subset of CTCs to enter and grow in the brain.

This article is highlighted in the In This Issue feature, p. 1
Data from Single-Cell Analysis Reveals Fibroblast Clusters Linked to Immunotherapy Resistance in Cancer
Authors: Kieffer Yann , Hocine Hocine R. , Gentric Géraldine , Pelon Floriane , Bernard Charles , Bourachot Brigitte , Lameiras Sonia , Albergante Luca , Bonneau Claire , Guyard Alice , Tarte Karin , Zinovyev Andrei , Baulande Sylvain , Zalcman Gerard , Vincent-Salomon Anne , Mechta-Grigoriou Fatima
Published: April 2023

Abstract
A subset of cancer-associated fibroblasts (FAP+/CAF-S1) mediates immunosuppression in breast cancers, but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19,000 single CAF-S1 fibroblasts from breast cancer. We validate the five most abundant clusters by flow cytometry and in silico analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extracellular matrix proteins and TGFβ signaling, respectively, are indicative of primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 and CTLA4 protein levels in regulatory T lymphocytes (Tregs), which, in turn, increases CAF-S1 cluster 3/TGFβ-myCAF cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance.
Significance:
Our work provides a significant advance in characterizing and understanding FAP+ CAF in cancer. We reached a high resolution at single-cell level, which enabled us to identify specific clusters associated with immunosuppression and immunotherapy resistance. Identification of cluster-specific signatures paves the way for therapeutic options in combination with immunotherapies.

This article is highlighted in the In This Issue feature, p. 1241
Data from Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia
Authors: Woyach Jennifer A. , Blachly James S. , Rogers Kerry A. , Bhat Seema A. , Jianfar Mojgan , Lozanski Gerard , Weiss David M. , Andersen Barbara L. , Gulrajani Michael , Frigault Melanie M. , Hamdy Ahmed , Izumi Raquel , Munugalavadla Veerendra , Quah Cheng , Wang Min-Hui , Byrd John C.
Published: April 2023

Abstract
Acalabrutinib is a selective irreversible Bruton tyrosine kinase (BTK) inhibitor that does not affect IL2-associated tyrosine kinase or antibody-dependent cellular cytotoxicity, making it an attractive candidate for combination therapy with anti-CD20 antibodies. We investigated acalabrutinib plus obinutuzumab in a phase Ib/II study (NCT02296918) of patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL). Nineteen treatment-naïve and 26 relapsed/refractory patients were treated with acalabrutinib (100 mg twice daily) until progression and obinutuzumab (cycle 1: 100 mg day 1, 900 mg day 2, 1000 mg days 8 and 15; cycles 2–6: 1,000 mg day 1). Grade 3/4 adverse events occurred in 71% of patients. Overall response rates were 95% (treatment-naïve) and 92% (relapsed/refractory). Thirty-two percent of treatment-naïve and 8% of relapsed/refractory patients achieved complete remission. At 36 months, 94% (treatment-naïve) and 88% (relapsed/refractory) were progression free. Acalabrutinib plus obinutuzumab was well tolerated, producing high and durable responses in treatment-naïve and relapsed/refractory CLL.
Significance:
Rituximab plus the less selective BTK inhibitor ibrutinib has not shown benefit in CLL; however, the selective BTK inhibitor acalabrutinib plus the antibody-dependent cellular cytotoxicity–enhanced antibody obinutuzumab yielded durable responses that deepened over time in treatment-naïve and relapsed/refractory CLL, supporting the evaluation of this approach in larger, comparative studies in CLL.

This article is highlighted in the In This Issue feature, p. 327
Data from Somatic Mutations Drive Specific, but Reversible, Epigenetic Heterogeneity States in AML
Authors: Li Sheng , Chen Xiaowen , Wang Jiahui , Meydan Cem , Glass Jacob L. , Shih Alan H. , Delwel Ruud , Levine Ross L. , Mason Christopher E. , Melnick Ari M.
Published: April 2023

Abstract
Epigenetic allele diversity is linked to inferior prognosis in acute myeloid leukemia (AML). However, the source of epiallele heterogeneity in AML is unknown. Herein we analyzed epiallele diversity in a genetically and clinically annotated AML cohort. Notably, AML driver mutations linked to transcription factors and favorable outcome are associated with epigenetic destabilization in a defined set of susceptible loci. In contrast, AML subtypes linked to inferior prognosis manifest greater abundance and highly stochastic epiallele patterning. We report an epiallele outcome classifier supporting the link between epigenetic diversity and treatment failure. Mouse models with TET2 or IDH2 mutations show that epiallele diversity is especially strongly induced by IDH mutations, precedes transformation to AML, and is enhanced by cooperation between somatic mutations. Furthermore, epiallele complexity was partially reversed by epigenetic therapies in AML driven by TET2/IDH2, suggesting that epigenetic therapy might function in part by reducing population complexity and fitness of AMLs.
Significance:
We show for the first time that epigenetic clonality is directly linked to specific mutations and that epigenetic allele diversity precedes and potentially contributes to malignant transformation. Furthermore, epigenetic clonality is reversible with epigenetic therapy agents.

This article is highlighted in the In This Issue feature, p. 1775
Data from Tuning the Antigen Density Requirement for CAR T-cell Activity
Authors: Majzner Robbie G. , Rietberg Skyler P. , Sotillo Elena , Dong Rui , Vachharajani Vipul T. , Labanieh Louai , Myklebust June H. , Kadapakkam Meena , Weber Evan W. , Tousley Aidan M. , Richards Rebecca M. , Heitzeneder Sabine , Nguyen Sang M. , Wiebking Volker , Theruvath Johanna , Lynn Rachel C. , Xu Peng , Dunn Alexander R. , Vale Ronald D. , Mackall Crystal L.
Published: April 2023

Abstract
Insufficient reactivity against cells with low antigen density has emerged as an important cause of chimeric antigen receptor (CAR) T-cell resistance. Little is known about factors that modulate the threshold for antigen recognition. We demonstrate that CD19 CAR activity is dependent upon antigen density and that the CAR construct in axicabtagene ciloleucel (CD19-CD28ζ) outperforms that in tisagenlecleucel (CD19-4-1BBζ) against antigen-low tumors. Enhancing signal strength by including additional immunoreceptor tyrosine-based activation motifs (ITAM) in the CAR enables recognition of low-antigen-density cells, whereas ITAM deletions blunt signal and increase the antigen density threshold. Furthermore, replacement of the CD8 hinge-transmembrane (H/T) region of a 4-1BBζ CAR with a CD28-H/T lowers the threshold for CAR reactivity despite identical signaling molecules. CARs incorporating a CD28-H/T demonstrate a more stable and efficient immunologic synapse. Precise design of CARs can tune the threshold for antigen recognition and endow 4-1BBζ-CARs with enhanced capacity to recognize antigen-low targets while retaining a superior capacity for persistence.
Significance:
Optimal CAR T-cell activity is dependent on antigen density, which is variable in many cancers, including lymphoma and solid tumors. CD28ζ-CARs outperform 4-1BBζ-CARs when antigen density is low. However, 4-1BBζ-CARs can be reengineered to enhance activity against low-antigen-density tumors while maintaining their unique capacity for persistence.

This article is highlighted in the In This Issue feature, p. 627
Data from Somatic HLA Class I Loss Is a Widespread Mechanism of Immune Evasion Which Refines the Use of Tumor Mutational Burden as a Biomarker of Checkpoint Inhibitor Response
Authors: Montesion Meagan , Murugesan Karthikeyan , Jin Dexter X. , Sharaf Radwa , Sanchez Nora , Guria Ameet , Minker Max , Li Gerald , Fisher Virginia , Sokol Ethan S. , Pavlick Dean C. , Moore Jay A. , Braly Alan , Singal Gaurav , Fabrizio David , Comment Leah A. , Rizvi Naiyer A. , Alexander Brian M. , Frampton Garrett M. , Hegde Priti S. , Albacker Lee A.
Published: April 2023

Abstract
Neoantigen presentation arises as a result of tumor-specific mutations and is a critical component of immune surveillance that can be abrogated by somatic LOH of the human leukocyte antigen class I (HLA-I) locus. To understand the role of HLA-I LOH in oncogenesis and treatment, we utilized a pan-cancer genomic dataset of 83,644 patient samples, a small subset of which had treatment outcomes with immune checkpoint inhibitors (ICI). HLA-I LOH was common (17%) and unexpectedly had a nonlinear relationship with tumor mutational burden (TMB). HLA-I LOH was frequent at intermediate TMB, yet prevalence decreased above 30 mutations/megabase, suggesting highly mutated tumors require alternate immune evasion mechanisms. In ICI-treated patients with nonsquamous non–small cell lung cancer, HLA-I LOH was a significant negative predictor of overall survival. Survival prediction improved when combined with TMB, suggesting TMB with HLA-I LOH may better identify patients likely to benefit from ICIs.
Significance:
This work shows the pan-cancer landscape of HLA-I LOH, revealing an unexpected “Goldilocks” relationship between HLA-I LOH and TMB, and demonstrates HLA-I LOH as a significant negative predictor of outcomes after ICI treatment. These data informed a combined predictor of outcomes after ICI and have implications for tumor vaccine development.

This article is highlighted in the In This Issue feature, p. 211
Data from Pharmacologic Suppression of B7-H4 Glycosylation Restores Antitumor Immunity in Immune-Cold Breast Cancers
Authors: Song Xinxin , Zhou Zhuan , Li Hongchun , Xue Yifan , Lu Xinghua , Bahar Ivet , Kepp Oliver , Hung Mien-Chie , Kroemer Guido , Wan Yong
Published: April 2023

Abstract
Despite widespread utilization of immunotherapy, treating immune-cold tumors has proved to be a challenge. Here, we report that expression of the immune checkpoint molecule B7-H4 is prevalent among immune-cold triple-negative breast cancers (TNBC), where its expression inversely correlates with that of PD-L1. Glycosylation of B7-H4 interferes with its interaction/ubiquitination by AMFR, resulting in B7-H4 stabilization. B7-H4 expression inhibits doxorubicin-induced cell death through the suppression of eIF2α phosphorylation required for calreticulin exposure vis-à-vis the cancer cells. NGI-1, which inhibits B7-H4 glycosylation causing its ubiquitination and subsequent degradation, improves the immunogenic properties of cancer cells treated with doxorubicin, enhancing their phagocytosis by dendritic cells and their capacity to elicit CD8+ IFNγ-producing T-cell responses. In preclinical models of TNBC, a triple combination of NGI-1, camsirubicin (a noncardiotoxic doxorubicin analogue) and PD-L1 blockade was effective in reducing tumor growth. Collectively, our findings uncover a strategy for targeting the immunosuppressive molecule B7-H4.
Significance:
This work unravels the regulation of B7-H4 stability by ubiquitination and glycosylation, which affects tumor immunogenicity, particularly regarding immune-cold breast cancers. The inhibition of B7-H4 glycosylation can be favorably combined with immunogenic chemotherapy and PD-L1 blockade to achieve superior immuno-infiltration of cold tumors, as well as improved tumor growth control.

See related commentary by Pearce and Läubli, p. 1789.

This article is highlighted in the In This Issue feature, p. 1775
Data from Distinct Colorectal Cancer–Associated APC Mutations Dictate Response to Tankyrase Inhibition
Authors: Schatoff Emma M. , Goswami Sukanya , Zafra Maria Paz , Foronda Miguel , Shusterman Michael , Leach Benjamin I. , Katti Alyna , Diaz Bianca J. , Dow Lukas E.
Published: April 2023

Abstract
The majority of colorectal cancers show hyperactivated WNT signaling due to inactivating mutations in the adenomatous polyposis coli (APC) tumor suppressor. Genetically restoring APC suppresses WNT and induces rapid and sustained tumor regression, implying that reengaging this endogenous tumor-suppressive mechanism may be an effective therapeutic strategy. Here, using new animal models, human cell lines, and ex vivo organoid cultures, we show that tankyrase (TNKS) inhibition can control WNT hyperactivation and provide long-term tumor control in vivo, but that effective responses are critically dependent on how APC is disrupted. Mutant APC proteins truncated within the mutation cluster region physically engage the destruction complex and suppress the WNT transcriptional program, while APC variants with early truncations (e.g., ApcMin) show limited interaction with AXIN1 and β-catenin, and do not respond to TNKS blockade. Together, this work shows that TNKS inhibition, like APC restoration, can reestablish endogenous control of WNT/β-catenin signaling, but that APC genotype is a crucial determinant of this response.
Significance:
This study reveals how subtle changes to the mutations in a critical colorectal tumor suppressor, APC, influence the cellular response to a targeted therapy. It underscores how investigating the specific genetic alterations that occur in human cancer can identify important biological mechanisms of drug response and resistance.

This article is highlighted in the In This Issue feature, p. 1325
Data from Unique Neoantigens Arise from Somatic Mutations in Patients with Gastrointestinal Cancers
Authors: Parkhurst Maria R. , Robbins Paul F. , Tran Eric , Prickett Todd D. , Gartner Jared J. , Jia Li , Ivey Gabriel , Li Yong F. , El-Gamil Mona , Lalani Almin , Crystal Jessica S. , Sachs Abraham , Groh Eric , Ray Satyajit , Ngo Lien T. , Kivitz Scott , Pasetto Anna , Yossef Rami , Lowery Frank J. , Goff Stephanie L. , Lo Winifred , Cafri Gal , Deniger Drew C. , Malekzadeh Parisa , Ahmadzadeh Mojgan , Wunderlich John R. , Somerville Robert P.T. , Rosenberg Steven A.
Published: April 2023

Abstract
Immunotherapies can mediate regression of human tumors with high mutation rates, but responses are rarely observed in patients with common epithelial cancers. This raises the question of whether patients with these common cancers harbor T lymphocytes that recognize mutant proteins expressed by autologous tumors that may represent ideal targets for immunotherapy. Using high-throughput immunologic screening of mutant gene products identified via whole-exome sequencing, we identified neoantigen-reactive tumor-infiltrating lymphocytes (TIL) from 62 of 75 (83%) patients with common gastrointestinal cancers. In total, 124 neoantigen-reactive TIL populations were identified, and all but one of the neoantigenic determinants were unique. The results of in vitro T-cell recognition assays demonstrated that 1.6% of the gene products encoded by somatic nonsynonymous mutations were immunogenic. These findings demonstrate that the majority of common epithelial cancers elicit immune recognition and open possibilities for cell-based immunotherapies for patients bearing these cancers.
Significance:
TILs cultured from 62 of 75 (83%) patients with gastrointestinal cancers recognized neoantigens encoded by 1.6% of somatic mutations expressed by autologous tumor cells, and 99% of the neoantigenic determinants appeared to be unique and not shared between patients.

This article is highlighted in the In This Issue feature, p. 983