bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition
Authors: Ennishi Daisuke , Takata Katsuyoshi , Béguelin Wendy , Duns Gerben , Mottok Anja , Farinha Pedro , Bashashati Ali , Saberi Saeed , Boyle Merrill , Meissner Barbara , Ben-Neriah Susana , Woolcock Bruce W. , Telenius Adèle , Lai Daniel , Teater Matt , Kridel Robert , Savage Kerry J. , Sehn Laurie H. , Morin Ryan D. , Marra Marco A. , Shah Sohrab P. , Connors Joseph M. , Gascoyne Randy D. , Scott David W. , Melnick Ari M. , Steidl Christian
Published: April 2023

Abstract
We performed a genomic, transcriptomic, and immunophenotypic study of 347 patients with diffuse large B-cell lymphoma (DLBCL) to uncover the molecular basis underlying acquired deficiency of MHC expression. Low MHC-II expression defines tumors originating from the centroblast-rich dark zone of the germinal center (GC) that was associated with inferior prognosis. MHC-II–deficient tumors were characterized by somatically acquired gene mutations reducing MHC-II expression and a lower amount of tumor-infiltrating lymphocytes. In particular, we demonstrated a strong enrichment of EZH2 mutations in both MHC-I– and MHC-II–negative primary lymphomas, and observed reduced MHC expression and T-cell infiltrates in murine lymphoma models expressing mutant Ezh2Y641. Of clinical relevance, EZH2 inhibitors significantly restored MHC expression in EZH2-mutated human DLBCL cell lines. Hence, our findings suggest a tumor progression model of acquired immune escape in GC-derived lymphomas and pave the way for development of complementary therapeutic approaches combining immunotherapy with epigenetic reprogramming.
Significance:
We demonstrate how MHC-deficient lymphoid tumors evolve in a cell-of-origin–specific context. Specifically, EZH2 mutations were identified as a genetic mechanism underlying acquired MHC deficiency. The paradigmatic restoration of MHC expression by EZH2 inhibitors provides the rationale for synergistic therapies combining immunotherapies with epigenetic reprogramming to enhance tumor recognition and elimination.

See related commentary by Velcheti et al., p. 472.

This article is highlighted in the In This Issue feature, p. 453
Data from ADAMDEC1 Maintains a Growth Factor Signaling Loop in Cancer Stem Cells
Authors: Jimenez-Pascual Ana , Hale James S. , Kordowski Anja , Pugh Jamie , Silver Daniel J. , Bayik Defne , Roversi Gustavo , Alban Tyler J. , Rao Shilpa , Chen Rui , McIntyre Thomas M. , Colombo Giorgio , Taraboletti Giulia , Holmberg Karl O. , Forsberg-Nilsson Karin , Lathia Justin D. , Siebzehnrubl Florian A.
Published: April 2023

Abstract
Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSC), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs consisting of an atypical metalloproteinase, ADAMDEC1, secreted by GSCs. ADAMDEC1 rapidly solubilizes FGF2 to stimulate FGFR1 expressed on GSCs. FGFR1 signaling induces upregulation of ZEB1 via ERK1/2 that regulates ADAMDEC1 expression through miR-203, creating a positive feedback loop. Genetic or pharmacologic targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM.
Significance:
Cancer stem cells (CSC) drive tumor growth in many cancers including GBM. We identified a novel sheddase, ADAMDEC1, which initiates an FGF autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce GBM growth.

This article is highlighted in the In This Issue feature, p. 1469
Data from Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers
Authors: Seguin Laetitia , Camargo Maria F. , Wettersten Hiromi I. , Kato Shumei , Desgrosellier Jay S. , von Schalscha Tami , Elliott Kathryn C. , Cosset Erika , Lesperance Jacqueline , Weis Sara M. , Cheresh David A.
Published: April 2023

Abstract
Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting αvβ3/galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate αvβ3-expressing KRAS-mutant lung and pancreatic cancer patient–derived xenografts and spontaneous tumors in mice. Our work reveals galectin-3 as a druggable target for KRAS-addicted lung and pancreas cancers, and indicates integrin αvβ3 as a biomarker to identify susceptible tumors.

Significance: There is a significant unmet need for therapies targeting KRAS-mutant cancers. Here, we identify integrin αvβ3 as a biomarker to identify mutant KRAS–addicted tumors that are highly sensitive to inhibition of galectin-3, a glycoprotein that binds to integrin αvβ3 to promote KRAS-mediated activation of AKT. Cancer Discov; 7(12); 1464–79. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1355
Data from In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma
Authors: Li Fei , Huang Qingyuan , Luster Troy A. , Hu Hai , Zhang Hua , Ng Wai-Lung , Khodadadi-Jamayran Alireza , Wang Wei , Chen Ting , Deng Jiehui , Ranieri Michela , Fang Zhaoyuan , Pyon Val , Dowling Catríona M. , Bagdatlioglu Ece , Almonte Christina , Labbe Kristen , Silver Heather , Rabin Alexandra R. , Jani Kandarp , Tsirigos Aristotelis , Papagiannakopoulos Thales , Hammerman Peter S. , Velcheti Vamsidhar , Freeman Gordon J. , Qi Jun , Miller George , Wong Kwok-Kin
Published: April 2023

Abstract
Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with KRAS-mutant lung adenocarcinoma (LUAD) remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses—such as epigenetic modulation of antitumor immunity—is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused single guide RNA library and performed an in vivo CRISPR screen in a KrasG12D/Trp53−/− LUAD model. Our data showed that loss of the histone chaperone Asf1a in tumor cells sensitizes tumors to anti–PD-1 treatment. Mechanistic studies revealed that tumor cell–intrinsic Asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T-cell activation in combination with anti–PD-1. Our results provide a rationale for a novel combination therapy consisting of ASF1A inhibition and anti–PD-1 immunotherapy.
Significance:
Using an in vivo epigenetic CRISPR screen, we identified Asf1a as a critical regulator of LUAD sensitivity to anti–PD-1 therapy. Asf1a deficiency synergized with anti–PD-1 immunotherapy by promoting M1-like macrophage polarization and T-cell activation. Thus, we provide a new immunotherapeutic strategy for this subtype of patients with LUAD.

See related commentary by Menzel and Black, p. 179.

This article is highlighted in the In This Issue feature, p. 161
Data from Histone Lysine Methylation Dynamics Control EGFR DNA Copy-Number Amplification
Authors: Clarke Thomas L. , Tang Ran , Chakraborty Damayanti , Van Rechem Capucine , Ji Fei , Mishra Sweta , Ma Anqi , Kaniskan H. Ümit , Jin Jian , Lawrence Michael S. , Sadreyev Ruslan I. , Whetstine Johnathan R.
Published: April 2023

Abstract
Acquired chromosomal DNA copy gains are a feature of many tumors; however, the mechanisms that underpin oncogene amplification are poorly understood. Recent studies have begun to uncover the importance of epigenetic states and histone lysine methyltransferases (KMT) and demethylases (KDM) in regulating transient site-specific DNA copy-number gains (TSSG). In this study, we reveal a critical interplay between a myriad of lysine methyltransferases and demethylases in modulating H3K4/9/27 methylation balance to control extrachromosomal amplification of the EGFR oncogene. This study further establishes that cellular signals (hypoxia and EGF) are able to directly promote EGFR amplification through modulation of the enzymes controlling EGFR copy gains. Moreover, we demonstrate that chemical inhibitors targeting specific KMTs and KDMs are able to promote or block extrachromosomal EGFR amplification, which identifies potential therapeutic strategies for controlling EGFR copy-number heterogeneity in cancer, and, in turn, drug response.
Significance:
This study identifies a network of epigenetic factors and cellular signals that directly control EGFR DNA amplification. We demonstrate that chemical inhibitors targeting enzymes controlling this amplification can be used to rheostat EGFR copy number, which uncovers therapeutic opportunities for controlling EGFR DNA amplification heterogeneity and the associated drug response.

This article is highlighted in the In This Issue feature, p. 161
Data from Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma
Authors: Mondello Patrizia , Tadros Saber , Teater Matt , Fontan Lorena , Chang Aaron Y. , Jain Neeraj , Yang Haopeng , Singh Shailbala , Ying Hsia-Yuan , Chu Chi-Shuen , Ma Man Chun John , Toska Eneda , Alig Stefan , Durant Matthew , de Stanchina Elisa , Ghosh Sreejoyee , Mottok Anja , Nastoupil Loretta , Neelapu Sattva S. , Weigert Oliver , Inghirami Giorgio , Baselga José , Younes Anas , Yee Cassian , Dogan Ahmet , Scheinberg David A. , Roeder Robert G. , Melnick Ari M. , Green Michael R.
Published: April 2023

Abstract
CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6–HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse CREBBP-mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infiltrating lymphocytes to kill DLBCL cells in an MHC class I and II–dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas.
Significance:
We have leveraged the molecular characterization of different types of CREBBP mutations to define a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBP-mutant cells in tandem with promoting antitumor immunity.

This article is highlighted in the In This Issue feature, p. 327
Data from EZH2-Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress
Authors: León Theresa E. , Rapoz-D'Silva Tanya , Bertoli Cosetta , Rahman Sunniyat , Magnussen Michael , Philip Brian , Farah Nadine , Richardson Simon E. , Ahrabi Sara , Guerra-Assunção José Afonso , Gupta Rajeev , Nacheva Elisabeth P. , Henderson Stephen , Herrero Javier , Linch David C. , de Bruin Robertus A.M. , Mansour Marc R.
Published: April 2023

Abstract
Loss-of-function mutations of EZH2, the enzymatic component of PRC2, have been associated with poor outcome and chemotherapy resistance in T-cell acute lymphoblastic leukemia (T-ALL). Using isogenic T-ALL cells, with and without CRISPR/Cas9–induced EZH2-inactivating mutations, we performed a cell-based synthetic lethal drug screen. EZH2-deficient cells exhibited increased sensitivity to structurally diverse inhibitors of CHK1, an interaction that could be validated genetically. Furthermore, small-molecule inhibition of CHK1 had efficacy in delaying tumor progression in isogenic EZH2-deficient, but not EZH2 wild-type, T-ALL cells in vivo, as well as in a primary cell model of PRC2-mutant ALL. Mechanistically, EZH2 deficiency resulted in a gene-expression signature of immature T-ALL cells, marked transcriptional upregulation of MYCN, increased replication stress, and enhanced dependency on CHK1 for cell survival. Finally, we demonstrate this phenotype is mediated through derepression of a distal PRC2-regulated MYCN enhancer. In conclusion, we highlight a novel and clinically exploitable pathway in high-risk EZH2-mutated T-ALL.
Significance:
Loss-of-function mutations of PRC2 genes are associated with chemotherapy resistance in T-ALL, yet no specific therapy for this aggressive subtype is currently clinically available. Our work demonstrates that loss of EZH2 activity leads to MYCN-driven replication stress, resulting in increased sensitivity to CHK1 inhibition, a finding with immediate clinical relevance.

This article is highlighted in the In This Issue feature, p. 890
Data from Identification of BBOX1 as a Therapeutic Target in Triple-Negative Breast Cancer
Authors: Liao Chengheng , Zhang Yang , Fan Cheng , Herring Laura E. , Liu Juan , Locasale Jason W. , Takada Mamoru , Zhou Jin , Zurlo Giada , Hu Lianxin , Simon Jeremy M. , Ptacek Travis S. , Andrianov Victor G. , Loza Einars , Peng Yan , Yang Huanghe , Perou Charles M. , Zhang Qing
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease. Because of its heterogeneity and lack of hormone receptors or HER2 expression, targeted therapy is limited. Here, by performing a functional siRNA screening for 2-OG–dependent enzymes, we identified gamma-butyrobetaine hydroxylase 1 (BBOX1) as an essential gene for TNBC tumorigenesis. BBOX1 depletion inhibits TNBC cell growth while not affecting normal breast cells. Mechanistically, BBOX1 binds with the calcium channel inositol-1,4,5-trisphosphate receptor type 3 (IP3R3) in an enzymatic-dependent manner and prevents its ubiquitination and proteasomal degradation. BBOX1 depletion suppresses IP3R3-mediated endoplasmic reticulum calcium release, therefore impairing calcium-dependent energy-generating processes including mitochondrial respiration and mTORC1-mediated glycolysis, which leads to apoptosis and impaired cell-cycle progression in TNBC cells. Therapeutically, genetic depletion or pharmacologic inhibition of BBOX1 inhibits TNBC tumor growth in vitro and in vivo. Our study highlights the importance of targeting the previously uncharacterized BBOX1–IP3R3–calcium oncogenic signaling axis in TNBC.
Significance:
We provide evidence from unbiased screens that BBOX1 is a potential therapeutic target in TNBC and that genetic knockdown or pharmacologic inhibition of BBOX1 leads to decreased TNBC cell fitness. This study lays the foundation for developing effective BBOX1 inhibitors for treatment of this lethal disease.

This article is highlighted in the In This Issue feature, p. 1611
Data from Triplet Therapy with Palbociclib, Taselisib, and Fulvestrant in PIK3CA-Mutant Breast Cancer and Doublet Palbociclib and Taselisib in Pathway-Mutant Solid Cancers
Authors: Pascual Javier , Lim Joline S.J. , Macpherson Iain R. , Armstrong Anne C. , Ring Alistair , Okines Alicia F.C. , Cutts Rosalind J. , Herrera-Abreu Maria Teresa , Garcia-Murillas Isaac , Pearson Alex , Hrebien Sarah , Gevensleben Heidrun , Proszek Paula Z. , Hubank Michael , Hills Margaret , King Jenny , Parmar Mona , Prout Toby , Finneran Laura , Malia Jason , Swales Karen E. , Ruddle Ruth , Raynaud Florence I. , Turner Alison , Hall Emma , Yap Timothy A. , Lopez Juanita S. , Turner Nicholas C.
Published: April 2023

Abstract
Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K inhibitors synergize in PIK3CA-mutant ER-positive HER2-negative breast cancer models. We conducted a phase Ib trial investigating the safety and efficacy of doublet CDK4/6 inhibitor palbociclib plus selective PI3K inhibitor taselisib in advanced solid tumors, and triplet palbociclib plus taselisib plus fulvestrant in 25 patients with PIK3CA-mutant, ER-positive HER2-negative advanced breast cancer. The triplet therapy response rate in PIK3CA-mutant, ER-positive HER2-negative cancer was 37.5% [95% confidence interval (CI), 18.8–59.4]. Durable disease control was observed in PIK3CA-mutant ER-negative breast cancer and other solid tumors with doublet therapy. Both combinations were well tolerated at pharmacodynamically active doses. In the triplet group, high baseline cyclin E1 expression associated with shorter progression-free survival (PFS; HR = 4.2; 95% CI, 1.3–13.1; P = 0.02). Early circulating tumor DNA (ctDNA) dynamics demonstrated high on-treatment ctDNA association with shorter PFS (HR = 5.2; 95% CI, 1.4–19.4; P = 0.04). Longitudinal plasma ctDNA sequencing provided genomic evolution evidence during triplet therapy.
SIGNIFICANCE:
The triplet of palbociclib, taselisib, and fulvestrant has promising efficacy in patients with heavily pretreated PIK3CA-mutant ER-positive HER2-negative advanced breast cancer. A subset of patients with PIK3CA-mutant triple-negative breast cancer derived clinical benefit from palbociclib and taselisib doublet, suggesting a potential nonchemotherapy targeted approach for this population.

This article is highlighted in the In This Issue feature, p. 1
Data from Golgi Acidification by NHE7 Regulates Cytosolic pH Homeostasis in Pancreatic Cancer Cells
Authors: Galenkamp Koen M.O. , Sosicka Paulina , Jung Michael , Recouvreux M. Victoria , Zhang Yijuan , Moldenhauer Matthew R. , Brandi Giovanni , Freeze Hudson H. , Commisso Cosimo
Published: April 2023

Abstractabstract
Cancer cells reprogram their metabolism to meet elevated energy demands and favor glycolysis for energy production. This boost in glycolytic flux supports proliferation, but also generates acid in the form of hydrogen ions that must be eliminated from the cytoplasm to maintain the alkaline intracellular pH (pHi) associated with transformation. To cope with acid production, tumor cells employ ion transport systems, including the family of sodium–hydrogen exchangers (NHE). Here, we identify NHE7 as a novel regulator of pHi in pancreatic ductal adenocarcinoma (PDAC). We determine that NHE7 suppression causes alkalinization of the Golgi, leading to a buildup of cytosolic acid that diminishes tumor cell fitness mainly through the dysregulation of actin. Importantly, NHE7 knockdown in vivo leads to the abrogation of tumor growth. These results identify Golgi acidification as a mechanism to control pHi and point to the regulation of pHi as a possible therapeutic vulnerability in PDAC.
Significance:
NHE7 regulates cytosolic pH through Golgi acidification, which points to the Golgi as a “proton sink” for metabolic acid. Disruption of cytosolic pH homeostasis via NHE7 suppression compromises PDAC cell viability and tumor growth.

See related commentary by Ward and DeNicola, p. 768.

This article is highlighted in the In This Issue feature, p. 747
Data from Posttranslational Regulation of the Exon Skipping Machinery Controls Aberrant Splicing in Leukemia
Authors: Zhou Yalu , Han Cuijuan , Wang Eric , Lorch Adam H. , Serafin Valentina , Cho Byoung-Kyu , Gutierrez Diaz Blanca T. , Calvo Julien , Fang Celestia , Khodadadi-Jamayran Alireza , Tabaglio Tommaso , Marier Christian , Kuchmiy Anna , Sun Limin , Yacu George , Filip Szymon K. , Jin Qi , Takahashi Yoh-Hei , Amici David R. , Rendleman Emily J. , Rawat Radhika , Bresolin Silvia , Paganin Maddalena , Zhang Cheng , Li Hu , Kandela Irawati , Politanska Yuliya , Abdala-Valencia Hiam , Mendillo Marc L. , Zhu Ping , Palhais Bruno , Van Vlierberghe Pieter , Taghon Tom , Aifantis Iannis , Goo Young Ah , Guccione Ernesto , Heguy Adriana , Tsirigos Aristotelis , Wee Keng Boon , Mishra Rama K. , Pflumio Francoise , Accordi Benedetta , Basso Giuseppe , Ntziachristos Panagiotis
Published: April 2023

Abstract
Splicing alterations are common in diseases such as cancer, where mutations in splicing factor genes are frequently responsible for aberrant splicing. Here we present an alternative mechanism for splicing regulation in T-cell acute lymphoblastic leukemia (T-ALL) that involves posttranslational stabilization of the splicing machinery via deubiquitination. We demonstrate there are extensive exon skipping changes in disease, affecting proteasomal subunits, cell-cycle regulators, and the RNA machinery. We present that the serine/arginine-rich splicing factors (SRSF), controlling exon skipping, are critical for leukemia cell survival. The ubiquitin-specific peptidase 7 (USP7) regulates SRSF6 protein levels via active deubiquitination, and USP7 inhibition alters the exon skipping pattern and blocks T-ALL growth. The splicing inhibitor H3B-8800 affects splicing of proteasomal transcripts and proteasome activity and acts synergistically with proteasome inhibitors in inhibiting T-ALL growth. Our study provides the proof-of-principle for regulation of splicing factors via deubiquitination and suggests new therapeutic modalities in T-ALL.
Significance:
Our study provides a new proof-of-principle for posttranslational regulation of splicing factors independently of mutations in aggressive T-cell leukemia. It further suggests a new drug combination of splicing and proteasomal inhibitors, a concept that might apply to other diseases with or without mutations affecting the splicing machinery.

This article is highlighted in the In This Issue feature, p. 1241
Data from Single-Cell RNA Sequencing Reveals Stromal Evolution into LRRC15+ Myofibroblasts as a Determinant of Patient Response to Cancer Immunotherapy
Authors: Dominguez Claudia X. , Müller Sören , Keerthivasan Shilpa , Koeppen Hartmut , Hung Jeffrey , Gierke Sarah , Breart Beatrice , Foreman Oded , Bainbridge Travis W. , Castiglioni Alessandra , Senbabaoglu Yasin , Modrusan Zora , Liang Yuxin , Junttila Melissa R. , Klijn Christiaan , Bourgon Richard , Turley Shannon J.
Published: April 2023

Abstract
With only a fraction of patients responding to cancer immunotherapy, a better understanding of the entire tumor microenvironment is needed. Using single-cell transcriptomics, we chart the fibroblastic landscape during pancreatic ductal adenocarcinoma (PDAC) progression in animal models. We identify a population of carcinoma-associated fibroblasts (CAF) that are programmed by TGFβ and express the leucine-rich repeat containing 15 (LRRC15) protein. These LRRC15+ CAFs surround tumor islets and are absent from normal pancreatic tissue. The presence of LRRC15+ CAFs in human patients was confirmed in >80,000 single cells from 22 patients with PDAC as well as by using IHC on samples from 70 patients. Furthermore, immunotherapy clinical trials comprising more than 600 patients across six cancer types revealed elevated levels of the LRRC15+ CAF signature correlated with poor response to anti–PD-L1 therapy. This work has important implications for targeting nonimmune elements of the tumor microenvironment to boost responses of patients with cancer to immune checkpoint blockade therapy.
Significance:
This study describes the single-cell landscape of CAFs in pancreatic cancer during in vivo tumor evolution. A TGFβ-driven, LRRC15+ CAF lineage is associated with poor outcome in immunotherapy trial data comprising multiple solid-tumor entities and represents a target for combinatorial therapy.

This article is highlighted in the In This Issue feature, p. 161
Data from MAIT Cells Promote Tumor Initiation, Growth, and Metastases via Tumor MR1
Authors: Yan Juming , Allen Stacey , McDonald Elizabeth , Das Indrajit , Mak Jeffrey Y.W. , Liu Ligong , Fairlie David P. , Meehan Bronwyn S. , Chen Zhenjun , Corbett Alexandra J. , Varelias Antiopi , Smyth Mark J. , Teng Michele W.L.
Published: April 2023

Abstract
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that require MHC class I–related protein 1 (MR1) for their development. The role of MAIT cells in cancer is unclear, and to date no study has evaluated these cells in vivo in this context. Here, we demonstrated that tumor initiation, growth, and experimental lung metastasis were significantly reduced in Mr1−/− mice, compared with wild-type mice. The antitumor activity observed in Mr1−/− mice required natural killer (NK) and/or CD8+ T cells and IFNγ. Adoptive transfer of MAIT cells into Mr1−/− mice reversed metastasis reduction. Similarly, MR1-blocking antibodies decreased lung metastases and suppressed tumor growth. Following MR1 ligand exposure, some, but not all, mouse and human tumor cell lines upregulated MR1. Pretreatment of tumor cells with the stimulatory ligand 5-OP-RU or inhibitory ligand Ac-6-FP increased or decreased lung metastases, respectively. MR1-deleted tumors resulted in fewer metastases compared with parental tumor cells. MAIT cell suppression of NK-cell effector function was tumor-MR1–dependent and partially required IL17A. Our studies indicate that MAIT cells display tumor-promoting function by suppressing T and/or NK cells and that blocking MR1 may represent a new therapeutic strategy for cancer immunotherapy.
Significance:
Contradicting the perception that MAIT cells kill tumor cells, here MAIT cells promoted tumor initiation, growth, and metastasis. MR1-expressing tumor cells activated MAIT cells to reduce NK-cell effector function, partly in a host IL17A–dependent manner. MR1-blocking antibodies reduced tumor metastases and growth, and may represent a new class of cancer therapeutics.

This article is highlighted in the In This Issue feature, p. 1
Data from Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia
Authors: Cremer Anjali , Ellegast Jana M. , Alexe Gabriela , Frank Elizabeth S. , Ross Linda , Chu S. Haihua , Pikman Yana , Robichaud Amanda , Goodale Amy , Häupl Björn , Mohr Sebastian , Rao Arati V. , Walker Alison R. , Blachly James S. , Piccioni Federica , Armstrong Scott A. , Byrd John C. , Oellerich Thomas , Stegmaier Kimberly
Published: April 2023

Abstract
Spleen tyrosine kinase (SYK) is a nonmutated therapeutic target in acute myeloid leukemia (AML). Attempts to exploit SYK therapeutically in AML have shown promising results in combination with chemotherapy, likely reflecting induced mechanisms of resistance to single-agent treatment in vivo. We conducted a genome-scale open reading frame (ORF) resistance screen and identified activation of the RAS–MAPK–ERK pathway as one major mechanism of resistance to SYK inhibitors. This finding was validated in AML cell lines with innate and acquired resistance to SYK inhibitors. Furthermore, patients with AML with select mutations activating these pathways displayed early resistance to SYK inhibition. To circumvent SYK inhibitor therapy resistance in AML, we demonstrate that a MEK and SYK inhibitor combination is synergistic in vitro and in vivo. Our data provide justification for use of ORF screening to identify resistance mechanisms to kinase inhibitor therapy in AML lacking distinct mutations and to direct novel combination-based strategies to abrogate these.
Significance:
The integration of functional genomic screening with the study of mechanisms of intrinsic and acquired resistance in model systems and human patients identified resistance to SYK inhibitors through MAPK signaling in AML. The dual targeting of SYK and the MAPK pathway offers a combinatorial strategy to overcome this resistance.

This article is highlighted in the In This Issue feature, p. 161
Data from The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple-Negative Breast Cancer
Authors: Liu Hui , Paddock Marcia N. , Wang Haibin , Murphy Charles J. , Geck Renee C. , Navarro Adrija J. , Wulf Gerburg M. , Elemento Olivier , Haucke Volker , Cantley Lewis C. , Toker Alex
Published: April 2023

Abstract
Inactivation of the tumor suppressor lipid phosphatase INPP4B is common in triple-negative breast cancer (TNBC). We generated a genetically engineered TNBC mouse model deficient in INPP4B. We found a dose-dependent increase in tumor incidence in INPP4B homozygous and heterozygous knockout mice compared with wild-type (WT), supporting a role for INPP4B as a tumor suppressor in TNBC. Tumors derived from INPP4B knockout mice are enriched for AKT and MEK gene signatures. Consequently, mice with INPP4B deficiency are more sensitive to PI3K or MEK inhibitors compared with WT mice. Mechanistically, we found that INPP4B deficiency increases PI(3,4)P2 levels in endocytic vesicles but not at the plasma membrane. Moreover, INPP4B loss delays degradation of EGFR and MET, while promoting recycling of receptor tyrosine kinases (RTK), thus enhancing the duration and amplitude of signaling output upon growth factor stimulation. Therefore, INPP4B inactivation in TNBC promotes tumorigenesis by modulating RTK recycling and signaling duration.
Significance:
Inactivation of the lipid phosphatase INPP4B is frequent in TNBC. Using a genetically engineered mouse model, we show that INPP4B functions as a tumor suppressor in TNBC. INPP4B regulates RTK trafficking and degradation, such that loss of INPP4B prolongs both PI3K and ERK activation.

This article is highlighted in the In This Issue feature, p. 1079
Data from Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non–BRCA1/2-Mutant Cancers
Authors: Yap Timothy A. , Kristeleit Rebecca , Michalarea Vasiliki , Pettitt Stephen J. , Lim Joline S.J. , Carreira Suzanne , Roda Desamparados , Miller Rowan , Riisnaes Ruth , Miranda Susana , Figueiredo Ines , Rodrigues Daniel Nava , Ward Sarah , Matthews Ruth , Parmar Mona , Turner Alison , Tunariu Nina , Chopra Neha , Gevensleben Heidrun , Turner Nicholas C. , Ruddle Ruth , Raynaud Florence I. , Decordova Shaun , Swales Karen E. , Finneran Laura , Hall Emma , Rugman Paul , Lindemann Justin P.O. , Foxley Andrew , Lord Christopher J. , Banerji Udai , Plummer Ruth , Basu Bristi , Lopez Juanita S. , Drew Yvette , de Bono Johann S.
Published: April 2023

Abstract
Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)–deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K–AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K–AKT pathway alterations.
Significance:
In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic–pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K–AKT pathway alterations.

This article is highlighted in the In This Issue feature, p. 1426
Data from Oncogenic KRAS Induces NIX-Mediated Mitophagy to Promote Pancreatic Cancer
Authors: Humpton Timothy J. , Alagesan Brinda , DeNicola Gina M. , Lu Dan , Yordanov Georgi N. , Leonhardt Carl S. , Yao Melissa A. , Alagesan Priya , Zaatari Maya N. , Park Youngkyu , Skepper Jeremy N. , Macleod Kay F. , Perez-Mancera Pedro A. , Murphy Michael P. , Evan Gerard I. , Vousden Karen H. , Tuveson David A.
Published: April 2023

Abstract
Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (PanIN) lesions progress to PDAC. We identify the KRAS–NIX mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC.
Significance:
NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer.

This article is highlighted in the In This Issue feature, p. 1143
Data from First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma
Authors: Kim Richard D. , Sarker Debashis , Meyer Tim , Yau Thomas , Macarulla Teresa , Park Joong-Won , Choo Su Pin , Hollebecque Antoine , Sung Max W. , Lim Ho-Yeong , Mazzaferro Vincenzo , Trojan Joerg , Zhu Andrew X. , Yoon Jung-Hwan , Sharma Sunil , Lin Zhong-Zhe , Chan Stephen L. , Faivre Sandrine , Feun Lynn G. , Yen Chia-Jui , Dufour Jean-Francois , Palmer Daniel H. , Llovet Josep M. , Manoogian Melissa , Tugnait Meera , Stransky Nicolas , Hagel Margit , Kohl Nancy E. , Lengauer Christoph , Sherwin Cori Ann , Schmidt-Kittler Oleg , Hoeflich Klaus P. , Shi Hongliang , Wolf Beni B. , Kang Yoon-Koo
Published: April 2023

Abstract
Outcomes for patients with advanced hepatocellular carcinoma (HCC) remain poor despite recent progress in drug development. Emerging data implicate FGF19 as a potential HCC driver, suggesting its receptor, FGFR4, as a novel therapeutic target. We evaluated fisogatinib (BLU-554), a highly potent and selective oral FGFR4 inhibitor, in a phase I dose-escalation/dose-expansion study in advanced HCC using FGF19 expression measured by IHC as a biomarker for pathway activation. For dose escalation, 25 patients received 140 to 900 mg fisogatinib once daily; the maximum tolerated dose (600 mg once daily) was expanded in 81 patients. Fisogatinib was well tolerated; most adverse events were manageable, grade 1/2 gastrointestinal events, primarily diarrhea, nausea, and vomiting. Across doses, the overall response rate was 17% in FGF19-positive patients [median duration of response: 5.3 months (95% CI, 3.7–not reached)] and 0% in FGF19-negative patients. These results validate FGFR4 as a targetable driver in FGF19-positive advanced HCC.
Significance:
Fisogatinib elicited clinical responses in patients with tumor FGF19 overexpression in advanced HCC. These results validate the oncogenic driver role of the FGFR4 pathway in HCC and the use of FGF19 as a biomarker for patient selection.

See related commentary by Subbiah and Pal, p. 1646.

This article is highlighted in the In This Issue feature, p. 1631
Data from Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity
Authors: Hong Aayoung , Piva Marco , Liu Sixue , Hugo Willy , Lomeli Shirley H. , Zoete Vincent , Randolph Christopher E. , Yang Zhentao , Wang Yan , Lee Jordan J. , Lo Skylar J. , Sun Lu , Vega-Crespo Agustin , Garcia Alejandro J. , Shackelford David B. , Dubinett Steven M. , Scumpia Philip O. , Byrum Stephanie D. , Tackett Alan J. , Donahue Timothy R. , Michielin Olivier , Holmen Sheri L. , Ribas Antoni , Moriceau Gatien , Lo Roger S.
Published: April 2023

Abstract
MAPK targeting in cancer often fails due to MAPK reactivation. MEK inhibitor (MEKi) monotherapy provides limited clinical benefits but may serve as a foundation for combination therapies. Here, we showed that combining a type II RAF inhibitor (RAFi) with an allosteric MEKi durably prevents and overcomes acquired resistance among cancers with KRAS, NRAS, NF1, BRAFnon-V600, and BRAFV600 mutations. Tumor cell–intrinsically, type II RAFi plus MEKi sequester MEK in RAF complexes, reduce MEK/MEK dimerization, and uncouple MEK from ERK in acquired-resistant tumor subpopulations. Immunologically, this combination expands memory and activated/exhausted CD8+ T cells, and durable tumor regression elicited by this combination requires CD8+ T cells, which can be reinvigorated by anti–PD-L1 therapy. Whereas MEKi reduces dominant intratumoral T-cell clones, type II RAFi cotreatment reverses this effect and promotes T-cell clonotypic expansion. These findings rationalize the clinical development of type II RAFi plus MEKi and their further combination with PD-1/L1-targeted therapy.
Significance:
Type I RAFi + MEKi are indicated only in certain BRAFV600MUT cancers. In contrast, type II RAFi + MEKi are durably active against acquired MEKi resistance across broad cancer indications, which reveals exquisite MAPK addiction. Allosteric modulation of MAPK protein/protein interactions and temporal preservation of intratumoral CD8+ T cells are mechanisms that may be further exploited.

This article is highlighted in the In This Issue feature, p. 521
Data from Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition
Authors: Cai Sheng F. , Chu S. Haihua , Goldberg Aaron D. , Parvin Salma , Koche Richard P. , Glass Jacob L. , Stein Eytan M. , Tallman Martin S. , Sen Filiz , Famulare Christopher A. , Cusan Monica , Huang Chun-Hao , Chen Chun-Wei , Zou Lihua , Cordner Keith B. , DelGaudio Nicole L. , Durani Vidushi , Kini Mitali , Rex Madison , Tian Helen S. , Zuber Johannes , Baslan Timour , Lowe Scott W. , Rienhoff Hugh Y. , Letai Anthony , Levine Ross L. , Armstrong Scott A.
Published: April 2023

Abstract
The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin–driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor MECOM (EVI1) compared with leukemias derived from myeloid progenitors. Here, we compared leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for EVI1 in modulating p53 protein abundance and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 (LSD1) inhibitors in addition to classical genotoxic stresses. p53 loss of function in Evi1lo progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1hi leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant EVI1hi acute myeloid leukemia.
Significance:
We demonstrate that the cell of origin of leukemia initiation influences p53 activity and dictates therapeutic sensitivity to pharmacologic LSD1 inhibitors via the transcription factor EVI1. We show that drug resistance could be overcome in HSC-derived leukemias by combining LSD1 inhibition with venetoclax.

See related commentary by Gu et al., p. 1445.

This article is highlighted in the In This Issue feature, p. 1426
Data from Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast–Driven Nutritional Support and Immunosuppression
Authors: Francescone Ralph , Barbosa Vendramini-Costa Débora , Franco-Barraza Janusz , Wagner Jessica , Muir Alexander , Lau Allison N. , Gabitova Linara , Pazina Tatiana , Gupta Sapna , Luong Tiffany , Rollins Dustin , Malik Ruchi , Thapa Roshan J. , Restifo Diana , Zhou Yan , Cai Kathy Q. , Hensley Harvey H. , Tan Yinfei , Kruger Warren D. , Devarajan Karthik , Balachandran Siddharth , Klein-Szanto Andres J. , Wang Huamin , El-Deiry Wafik S. , Vander Heiden Matthew G. , Peri Suraj , Campbell Kerry S. , Astsaturov Igor , Cukierman Edna
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate and lacks effective therapeutics. Therefore, it is of paramount importance to identify new targets. Using multiplex data from patient tissue, three-dimensional coculturing in vitro assays, and orthotopic murine models, we identified Netrin G1 (NetG1) as a promoter of PDAC tumorigenesis. We found that NetG1+ cancer-associated fibroblasts (CAF) support PDAC survival, through a NetG1-mediated effect on glutamate/glutamine metabolism. Also, NetG1+ CAFs are intrinsically immunosuppressive and inhibit natural killer cell–mediated killing of tumor cells. These protumor functions are controlled by a signaling circuit downstream of NetG1, which is comprised of AKT/4E-BP1, p38/FRA1, vesicular glutamate transporter 1, and glutamine synthetase. Finally, blocking NetG1 with a neutralizing antibody stunts in vivo tumorigenesis, suggesting NetG1 as potential target in PDAC.
Significance:
This study demonstrates the feasibility of targeting a fibroblastic protein, NetG1, which can limit PDAC tumorigenesis in vivo by reverting the protumorigenic properties of CAFs. Moreover, inhibition of metabolic proteins in CAFs altered their immunosuppressive capacity, linking metabolism with immunomodulatory function.

See related commentary by Sherman, p. 230.

This article is highlighted in the In This Issue feature, p. 211
Data from Glioma Stem Cell–Specific Superenhancer Promotes Polyunsaturated Fatty-Acid Synthesis to Support EGFR Signaling
Authors: Gimple Ryan C. , Kidwell Reilly L. , Kim Leo J.Y. , Sun Tengqian , Gromovsky Anthony D. , Wu Qiulian , Wolf Megan , Lv Deguan , Bhargava Shruti , Jiang Li , Prager Briana C. , Wang Xiuxing , Ye Qing , Zhu Zhe , Zhang Guoxin , Dong Zhen , Zhao Linjie , Lee Derrick , Bi Junfeng , Sloan Andrew E. , Mischel Paul S. , Brown J. Mark , Cang Hu , Huan Tao , Mack Stephen C. , Xie Qi , Rich Jeremy N.
Published: April 2023

Abstract
Glioblastoma ranks among the most aggressive and lethal of all human cancers. Functionally defined glioma stem cells (GSC) contribute to this poor prognosis by driving therapeutic resistance and maintaining cellular heterogeneity. To understand the molecular processes essential for GSC maintenance and tumorigenicity, we interrogated the superenhancer landscapes of primary glioblastoma specimens and in vitro GSCs. GSCs epigenetically upregulated ELOVL2, a key polyunsaturated fatty-acid synthesis enzyme. Targeting ELOVL2 inhibited glioblastoma cell growth and tumor initiation. ELOVL2 depletion altered cellular membrane phospholipid composition, disrupted membrane structural properties, and diminished EGFR signaling through control of fatty-acid elongation. In support of the translational potential of these findings, dual targeting of polyunsaturated fatty-acid synthesis and EGFR signaling had a combinatorial cytotoxic effect on GSCs.
Significance:
Glioblastoma remains a devastating disease despite extensive characterization. We profiled epigenomic landscapes of glioblastoma to pinpoint cell state–specific dependencies and therapeutic vulnerabilities. GSCs utilize polyunsaturated fatty-acid synthesis to support membrane architecture, inhibition of which impairs EGFR signaling and GSC proliferation. Combinatorial targeting of these networks represents a promising therapeutic strategy.

See related commentary by Affronti and Wellen, p. 1161.

This article is highlighted in the In This Issue feature, p. 1143
Data from Innate αβ T Cells Mediate Antitumor Immunity by Orchestrating Immunogenic Macrophage Programming
Authors: Hundeyin Mautin , Kurz Emma , Mishra Ankita , Rossi Juan Andres Kochen , Liudahl Shannon M. , Leis Kenna R. , Mehrotra Harshita , Kim Mirhee , Torres Luisana E. , Ogunsakin Adesola , Link Jason , Sears Rosalie C. , Sivagnanam Shamilene , Goecks Jeremy , Islam K.M. Sadeq , Dolgalev Igor , Savadkar Shivraj , Wang Wei , Aykut Berk , Leinwand Joshua , Diskin Brian , Adam Salma , Israr Muhammad , Gelas Maeliss , Lish Justin , Chin Kathryn , Farooq Mohammad Saad , Wadowski Benjamin , Wu Jingjing , Shah Suhagi , Adeegbe Dennis O. , Pushalkar Smruti , Vasudevaraja Varshini , Saxena Deepak , Wong Kwok-Kin , Coussens Lisa M. , Miller George
Published: April 2023

Abstract
Unconventional T-lymphocyte populations are emerging as important regulators of tumor immunity. Despite this, the role of TCRαβ+CD4−CD8−NK1.1− innate αβ T cells (iαβT) in pancreatic ductal adenocarcinoma (PDA) has not been explored. We found that iαβTs represent ∼10% of T lymphocytes infiltrating PDA in mice and humans. Intratumoral iαβTs express a distinct T-cell receptor repertoire and profoundly immunogenic phenotype compared with their peripheral counterparts and conventional lymphocytes. iαβTs comprised ∼75% of the total intratumoral IL17+ cells. Moreover, iαβT-cell adoptive transfer is protective in both murine models of PDA and human organotypic systems. We show that iαβT cells induce a CCR5-dependent immunogenic macrophage reprogramming, thereby enabling marked CD4+ and CD8+ T-cell expansion/activation and tumor protection. Collectively, iαβTs govern fundamental intratumoral cross-talk between innate and adaptive immune populations and are attractive therapeutic targets.
Significance:
We found that iαβTs are a profoundly activated T-cell subset in PDA that slow tumor growth in murine and human models of disease. iαβTs induce a CCR5-dependent immunogenic tumor-associated macrophage program, T-cell activation and expansion, and should be considered as novel targets for immunotherapy.

See related commentary by Banerjee et al., p. 1164.

This article is highlighted in the In This Issue feature, p. 1143