bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from RTK-Dependent Inducible Degradation of Mutant PI3Kα Drives GDC-0077 (Inavolisib) Efficacy
Authors: Song Kyung W. , Edgar Kyle A. , Hanan Emily J. , Hafner Marc , Oeh Jason , Merchant Mark , Sampath Deepak , Nannini Michelle A. , Hong Rebecca , Phu Lilian , Forrest William F. , Stawiski Eric , Schmidt Stephen , Endres Nicholas , Guan Jane , Wallin Jeffrey J. , Cheong Jonathan , Plise Emile G. , Lewis Phillips Gail D. , Salphati Laurent , Heffron Timothy P. , Olivero Alan G. , Malek Shiva , Staben Steven T. , Kirkpatrick Donald S. , Dey Anwesha , Friedman Lori S.
Published: April 2023

Abstract
PIK3CA is one of the most frequently mutated oncogenes; the p110a protein it encodes plays a central role in tumor cell proliferation. Small-molecule inhibitors targeting the PI3K p110a catalytic subunit have entered clinical trials, with early-phase GDC-0077 studies showing antitumor activity and a manageable safety profile in patients with PIK3CA-mutant breast cancer. However, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent mutant p110a degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression. This study establishes a new strategy for identifying inhibitors that specifically target mutant tumors by selective degradation of the mutant oncoprotein and provide a strong rationale for pursuing PI3Kα degraders in patients with HER2-positive breast cancer.
Significance:
The PI3K inhibitors GDC-0077 and taselisib have a unique mechanism of action; both inhibitors lead to degradation of mutant p110a protein. The inhibitors that have the ability to trigger specific degradation of mutant p110a without significant change in wild-type p110a protein may result in improved therapeutic index in PIK3CA-mutant tumors.

See related commentary by Vanhaesebroeck et al., p. 20.

This article is highlighted in the In This Issue feature, p. 1
Data from Therapeutically Increasing MHC-I Expression Potentiates Immune Checkpoint Blockade
Authors: Gu Shengqing Stan , Zhang Wubing , Wang Xiaoqing , Jiang Peng , Traugh Nicole , Li Ziyi , Meyer Clifford , Stewig Blair , Xie Yingtian , Bu Xia , Manos Michael P. , Font-Tello Alba , Gjini Evisa , Lako Ana , Lim Klothilda , Conway Jake , Tewari Alok K. , Zeng Zexian , Sahu Avinash Das , Tokheim Collin , Weirather Jason L. , Fu Jingxin , Zhang Yi , Kroger Benjamin , Liang Jin Hua , Cejas Paloma , Freeman Gordon J. , Rodig Scott , Long Henry W. , Gewurz Benjamin E. , Hodi F. Stephen , Brown Myles , Liu X. Shirley
Published: April 2023

Abstract
Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Here, we combined FACS-based genome-wide CRISPR screens with a data-mining approach to identify drugs that can upregulate MHC-I without inducing PD-L1. CRISPR screening identified TRAF3, a suppressor of the NFκB pathway, as a negative regulator of MHC-I but not PD-L1. The Traf3-knockout gene expression signature is associated with better survival in ICB-naïve patients with cancer and better ICB response. We then screened for drugs with similar transcriptional effects as this signature and identified Second Mitochondria-derived Activator of Caspase (SMAC) mimetics. We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell–dependent killing, and adds to ICB efficacy. Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy.
Significance:
MHC-I loss or downregulation in cancer cells is a major mechanism of resistance to T cell–based immunotherapies. Our study reveals that birinapant may be used for patients with low baseline MHC-I to enhance ICB response. This represents promising immunotherapy opportunities given the biosafety profile of birinapant from multiple clinical trials.

This article is highlighted in the In This Issue feature, p. 1307
Data from AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia
Authors: Tirado-Gonzalez Irene , Descot Arnaud , Soetopo Devona , Nevmerzhitskaya Aleksandra , Schäffer Alexander , Kur Ivan-Maximilano , Czlonka Ewelina , Wachtel Carolin , Tsoukala Ioanna , Müller Luise , Schäfer Anna-Lena , Weitmann Maresa , Dinse Petra , Alberto Emily , Buck Michèle C. , Landry Jonathan JM. , Baying Bianka , Slotta-Huspenina Julia , Roesler Jenny , Harter Patrick N. , Kubasch Anne-Sophie , Meinel Jörn , Elwakeel Eiman , Strack Elisabeth , Quang Christine Tran , Abdel-Wahab Omar , Schmitz Marc , Weigert Andreas , Schmid Tobias , Platzbecker Uwe , Benes Vladimir , Ghysdael Jacques , Bonig Halvard , Götze Katharina S. , Rothlin Carla V. , Ghosh Sourav , Medyouf Hind
Published: April 2023

Abstract
Acute leukemias are systemic malignancies associated with a dire outcome. Because of low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages toward a tumor-promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates antileukemic immunity and elicits effective and lasting natural killer cell– and T cell–dependent immune response against naïve and treatment-resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD-1 checkpoint blockade in PD-1–refractory leukemias. Finally, we provide proof-of-concept that a clinical-grade AXL inhibitor can be used in combination with standard-of-care therapy to cure established leukemia, regardless of AXL expression in malignant cells.
Significance:
Alternatively primed myeloid cells predict negative outcome in leukemia. By demonstrating that leukemia cells actively evade immune control by engaging AXL receptor tyrosine kinase in macrophages and promoting their alternative priming, we identified a target which blockade, using a clinical-grade inhibitor, is vital to unleashing the therapeutic potential of myeloid-centered immunotherapy.

This article is highlighted in the In This Issue feature, p. 2659
Data from Mutations in the RAS/MAPK Pathway Drive Replication Repair–Deficient Hypermutated Tumors and Confer Sensitivity to MEK Inhibition
Authors: Campbell Brittany B. , Galati Melissa A. , Stone Simone C. , Riemenschneider Alexandra N. , Edwards Melissa , Sudhaman Sumedha , Siddaway Robert , Komosa Martin , Nunes Nuno M. , Nobre Liana , Morrissy A. Sorana , Zatzman Matthew , Zapotocky Michal , Joksimovic Lazar , Kalimuthu Sangeetha N. , Samuel David , Mason Gary , Bouffet Eric , Morgenstern Daniel A. , Aronson Melyssa , Durno Carol , Malkin David , Maris John M. , Taylor Michael D. , Shlien Adam , Pugh Trevor J. , Ohashi Pamela S. , Hawkins Cynthia E. , Tabori Uri
Published: April 2023

Abstract
The RAS/MAPK pathway is an emerging targeted pathway across a spectrum of both adult and pediatric cancers. Typically, this is associated with a single, well-characterized point mutation in an oncogene. Hypermutant tumors that harbor many somatic mutations may obscure the interpretation of such targetable genomic events. We find that replication repair–deficient (RRD) cancers, which are universally hypermutant and affect children born with RRD cancer predisposition, are enriched for RAS/MAPK mutations (P = 10−8). These mutations are not random, exist in subclones, and increase in allelic frequency over time. The RAS/MAPK pathway is activated both transcriptionally and at the protein level in patient-derived RRD tumors, and these tumors responded to MEK inhibition in vitro and in vivo. Treatment of patients with RAS/MAPK hypermutant gliomas reveals durable responses to MEK inhibition. Our observations suggest that hypermutant tumors may be addicted to oncogenic pathways, resulting in favorable response to targeted therapies.
Significance:
Tumors harboring a single RAS/MAPK driver mutation are targeted individually for therapeutic purposes. We find that in RRD hypermutant cancers, mutations in the RAS/MAPK pathway are enriched, highly expressed, and result in sensitivity to MEK inhibitors. Targeting an oncogenic pathway may provide therapeutic options for these hypermutant polyclonal cancers.

This article is highlighted in the In This Issue feature, p. 1307
Data from Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia
Authors: Malani Disha , Kumar Ashwini , Brück Oscar , Kontro Mika , Yadav Bhagwan , Hellesøy Monica , Kuusanmäki Heikki , Dufva Olli , Kankainen Matti , Eldfors Samuli , Potdar Swapnil , Saarela Jani , Turunen Laura , Parsons Alun , Västrik Imre , Kivinen Katja , Saarela Janna , Räty Riikka , Lehto Minna , Wolf Maija , Gjertsen Bjorn Tore , Mustjoki Satu , Aittokallio Tero , Wennerberg Krister , Heckman Caroline A. , Kallioniemi Olli , Porkka Kimmo
Published: April 2023

Abstract
We generated ex vivo drug-response and multiomics profiling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board (FPMTB) integrated clinical, molecular, and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of patients with AML, and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five patients with AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled the identification of drug response biomarkers, such as the association of IL15 overexpression with resistance to FLT3 inhibitors. Integration of molecular profiling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommendations, providing a paradigm for individualized implementation of functional precision cancer medicine.
Significance:
Oncogenomics data can guide clinical treatment decisions, but often such data are neither actionable nor predictive. Functional ex vivo drug testing contributes significant additional, clinically actionable therapeutic insights for individual patients with AML. Such data can be generated in four days, enabling rapid translation through FPMTB.

See related commentary by Letai, p. 290.

This article is highlighted in the In This Issue feature, p. 275
Data from ZFTA Translocations Constitute Ependymoma Chromatin Remodeling and Transcription Factors
Authors: Kupp Robert , Ruff Lisa , Terranova Sabrina , Nathan Erica , Ballereau Stephane , Stark Rory , Sekhar Reddy Chilamakuri Chandra , Hoffmann Nadin , Wickham-Rahrmann Katherine , Widdess Marcus , Arabzade Amir , Zhao Yanhua , Varadharajan Srinidhi , Zheng Tuyu , Murugesan Mohankumar , Pfister Stefan M. , Kawauchi Daisuke , Pajtler Kristian W. , Deneen Benjamin , Mack Stephen C. , Masih Katherine E. , Gryder Berkley E. , Khan Javed , Gilbertson Richard J.
Published: April 2023

Abstract
ZFTA (C11orf95)—a gene of unknown function—partners with a variety of transcriptional coactivators in translocations that drive supratentorial ependymoma, a frequently lethal brain tumor. Understanding the function of ZFTA is key to developing therapies that inhibit these fusion proteins. Here, using a combination of transcriptomics, chromatin immunoprecipitation sequencing, and proteomics, we interrogated a series of deletion-mutant genes to identify a tripartite transformation mechanism of ZFTA-containing fusions, including: spontaneous nuclear translocation, extensive chromatin binding, and SWI/SNF, SAGA, and NuA4/Tip60 HAT chromatin modifier complex recruitment. Thereby, ZFTA tethers fusion proteins across the genome, modifying chromatin to an active state and enabling its partner transcriptional coactivators to promote promiscuous expression of a transforming transcriptome. Using mouse models, we validate further those elements of ZFTA-fusion proteins that are critical for transformation—including ZFTA zinc fingers and partner gene transactivation domains—thereby unmasking vulnerabilities for therapeutic targeting.
Significance:
Ependymomas are hard-to-treat brain tumors driven by translocations between ZFTA and a variety of transcriptional coactivators. We dissect the transforming mechanism of these fusion proteins and identify protein domains indispensable for tumorigenesis, thereby providing insights into the molecular basis of ependymoma tumorigenesis and vulnerabilities for therapeutic targeting.

This article is highlighted in the In This Issue feature, p. 2113
Data from Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma
Authors: Riscal Romain , Bull Caroline J. , Mesaros Clementina , Finan Jennifer M. , Carens Madeleine , Ho Elaine S. , Xu Jimmy P. , Godfrey Jason , Brennan Paul , Johansson Mattias , Purdue Mark P. , Chanock Stephen J. , Mariosa Daniela , Timpson Nicholas J. , Vincent Emma E. , Keith Brian , Blair Ian A. , Skuli Nicolas , Simon M. Celeste
Published: April 2023

Abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by large intracellular lipid droplets containing free and esterified cholesterol; however, the functional significance of cholesterol accumulation in ccRCC cells is unknown. We demonstrate that, surprisingly, genes encoding cholesterol biosynthetic enzymes are repressed in ccRCC, suggesting a dependency on exogenous cholesterol. Mendelian randomization analyses based on 31,000 individuals indicate a causal link between elevated circulating high-density lipoprotein (HDL) cholesterol and ccRCC risk. Depriving ccRCC cells of either cholesterol or HDL compromises proliferation and survival in vitro and tumor growth in vivo; in contrast, elevated dietary cholesterol promotes tumor growth. Scavenger Receptor B1 (SCARB1) is uniquely required for cholesterol import, and inhibiting SCARB1 is sufficient to cause ccRCC cell-cycle arrest, apoptosis, elevated intracellular reactive oxygen species levels, and decreased PI3K/AKT signaling. Collectively, we reveal a cholesterol dependency in ccRCC and implicate SCARB1 as a novel therapeutic target for treating kidney cancer.
Significance:
We demonstrate that ccRCC cells are auxotrophic for exogenous cholesterol to maintain PI3K/AKT signaling pathway and ROS homeostasis. Blocking cholesterol import through the HDL transporter SCARB1 compromises ccRCC cell survival and tumor growth, suggesting a novel pharmacologic target for this disease.

This article is highlighted in the In This Issue feature, p. 2945
Data from MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression
Authors: Knight John R.P. , Alexandrou Constantinos , Skalka George L. , Vlahov Nikola , Pennel Kathryn , Officer Leah , Teodosio Ana , Kanellos Georgios , Gay David M. , May-Wilson Sebastian , Smith Ewan M. , Najumudeen Arafath K. , Gilroy Kathryn , Ridgway Rachel A. , Flanagan Dustin J. , Smith Rachael C.L. , McDonald Laura , MacKay Craig , Cheasty Anne , McArthur Kerri , Stanway Emma , Leach Joshua D. , Jackstadt Rene , Waldron Joseph A. , Campbell Andrew D. , Vlachogiannis Georgios , Valeri Nicola , Haigis Kevin M. , Sonenberg Nahum , Proud Christopher G. , Jones Neil P. , Swarbrick Martin E. , McKinnon Heather J. , Faller William J. , Le Quesne John , Edwards Joanne , Willis Anne E. , Bushell Martin , Sansom Owen J.
Published: April 2023

Abstract
KRAS-mutant colorectal cancers are resistant to therapeutics, presenting a significant problem for ∼40% of cases. Rapalogs, which inhibit mTORC1 and thus protein synthesis, are significantly less potent in KRAS-mutant colorectal cancer. Using Kras-mutant mouse models and mouse- and patient-derived organoids, we demonstrate that KRAS with G12D mutation fundamentally rewires translation to increase both bulk and mRNA-specific translation initiation. This occurs via the MNK/eIF4E pathway culminating in sustained expression of c-MYC. By genetic and small-molecule targeting of this pathway, we acutely sensitize KRASG12D models to rapamycin via suppression of c-MYC. We show that 45% of colorectal cancers have high signaling through mTORC1 and the MNKs, with this signature correlating with a 3.5-year shorter cancer-specific survival in a subset of patients. This work provides a c-MYC–dependent cotargeting strategy with remarkable potency in multiple Kras-mutant mouse models and metastatic human organoids and identifies a patient population that may benefit from its clinical application.
Significance:
KRAS mutation and elevated c-MYC are widespread in many tumors but remain predominantly untargetable. We find that mutant KRAS modulates translation, culminating in increased expression of c-MYC. We describe an effective strategy targeting mTORC1 and MNK in KRAS-mutant mouse and human models, pathways that are also commonly co-upregulated in colorectal cancer.

This article is highlighted in the In This Issue feature, p. 995
Data from Rates and Patterns of Clonal Oncogenic Mutations in the Normal Human Brain
Authors: Ganz Javier , Maury Eduardo A. , Becerra Basheer , Bizzotto Sara , Doan Ryan N. , Kenny Connor J. , Shin Taehwan , Kim Junho , Zhou Zinan , Ligon Keith L. , Lee Eunjung Alice , Walsh Christopher A.
Published: April 2023

Abstract
Although oncogenic mutations have been found in nondiseased, proliferative nonneural tissues, their prevalence in the human brain is unknown. Targeted sequencing of genes implicated in brain tumors in 418 samples derived from 110 individuals of varying ages, without tumor diagnoses, detected oncogenic somatic single-nucleotide variants (sSNV) in 5.4% of the brains, including IDH1R132H. These mutations were largely present in subcortical white matter and enriched in glial cells and, surprisingly, were less common in older individuals. A depletion of high-allele frequency sSNVs representing macroscopic clones with age was replicated by analysis of bulk RNA sequencing data from 1,816 nondiseased brain samples ranging from fetal to old age. We also describe large clonal copy number variants and that sSNVs show mutational signatures resembling those found in gliomas, suggesting that mutational processes of the normal brain drive early glial oncogenesis. This study helps understand the origin and early evolution of brain tumors.
Significance:
In the nondiseased brain, clonal oncogenic mutations are enriched in white matter and are less common in older individuals. We revealed early steps in acquiring oncogenic variants, which are essential to understanding brain tumor origins and building new mutational baselines for diagnostics.

This article is highlighted in the In This Issue feature, p. 1
Data from Direct and Indirect Regulators of Epithelial–Mesenchymal Transition–Mediated Immunosuppression in Breast Carcinomas
Authors: Dongre Anushka , Rashidian Mohammad , Eaton Elinor Ng , Reinhardt Ferenc , Thiru Prathapan , Zagorulya Maria , Nepal Sunita , Banaz Tuba , Martner Anna , Spranger Stefani , Weinberg Robert A.
Published: April 2023

Abstract
The epithelial-to-mesenchymal transition, which conveys epithelial (E) carcinoma cells to quasi-mesenchymal (qM) states, enables them to metastasize and acquire resistance to certain treatments. Murine tumors composed of qM mammary carcinoma cells assemble an immunosuppressive tumor microenvironment (TME) and develop resistance to anti-CTLA4 immune-checkpoint blockade (ICB) therapy, unlike their E counterparts. Importantly, minority populations of qM cells within a tumor can cross-protect their more E neighbors from immune attack. The underlying mechanisms of immunosuppression and cross-protection have been unclear. We demonstrate that abrogation of qM carcinoma cell–derived factors (CD73, CSF1, or SPP1) prevents the assembly of an immunosuppressive TME and sensitizes otherwise refractory qM tumors partially or completely to anti-CTLA4 ICB. Most strikingly, mixed tumors in which minority populations of carcinoma cells no longer express CD73 are now sensitized to anti-CTLA4 ICB. Finally, loss of CD73 also enhances the efficacy of anti-CTLA4 ICB during the process of metastatic colonization.
Significance:
Minority populations of qM carcinoma cells, which likely reside in human breast carcinomas, can cross-protect their E neighbors from immune attack. Understanding the mechanisms by which qM carcinoma cells resist antitumor immune attack can help identify signaling channels that can be interrupted to potentiate the efficacy of checkpoint blockade immunotherapies.

This article is highlighted in the In This Issue feature, p. 995
Data from Combined Inhibition of SHP2 and CXCR1/2 Promotes Antitumor T-cell Response in NSCLC
Authors: Tang Kwan Ho , Li Shuai , Khodadadi-Jamayran Alireza , Jen Jayu , Han Han , Guidry Kayla , Chen Ting , Hao Yuan , Fedele Carmine , Zebala John A. , Maeda Dean Y. , Christensen James G. , Olson Peter , Athanas Argus , Loomis Cynthia A. , Tsirigos Aristotelis , Wong Kwok-Kin , Neel Benjamin G.
Published: April 2023

Abstract
SHP2 inhibitors (SHP2i) alone and in various combinations are being tested in multiple tumors with overactivation of the RAS/ERK pathway. SHP2 plays critical roles in normal cell signaling; hence, SHP2is could influence the tumor microenvironment. We found that SHP2i treatment depleted alveolar and M2-like macrophages, induced tumor-intrinsic CCL5/CXCL10 secretion, and promoted B and T lymphocyte infiltration in Kras- and Egfr-mutant non–small cell lung cancer (NSCLC). However, treatment also increased intratumor granulocytic myeloid-derived suppressor cells (gMDSC) via tumor-intrinsic, NFκB-dependent production of CXCR2 ligands. Other RAS/ERK pathway inhibitors also induced CXCR2 ligands and gMDSC influx in mice, and CXCR2 ligands were induced in tumors from patients on KRASG12C inhibitor trials. Combined SHP2 (SHP099)/CXCR1/2 (SX682) inhibition depleted a specific cluster of S100a8/9hi gMDSCs, generated Klrg1+ CD8+ effector T cells with a strong cytotoxic phenotype but expressing the checkpoint receptor NKG2A, and enhanced survival in Kras- and Egfr-mutant models. Our results argue for testing RAS/ERK pathway/CXCR1/2/NKG2A inhibitor combinations in patients with NSCLC.
Significance:
Our study shows that inhibiting the SHP2/RAS/ERK pathway triggers NFκB-dependent upregulation of CXCR2 ligands and recruitment of S100A8hi gMDSCs, which suppress T cells. Combining SHP2/CXCR2 inhibitors blocks gMDSC immigration, resulting in enhanced Th1 polarization, induced CD8+KLRG1+ effector T cells with high cytotoxic activity, and improved survival in multiple NSCLC models.

This article is highlighted in the In This Issue feature, p. 1
Data from Clinical and Biological Subtypes of B-cell Lymphoma Revealed by Microenvironmental Signatures
Authors: Kotlov Nikita , Bagaev Alexander , Revuelta Maria V. , Phillip Jude M. , Cacciapuoti Maria Teresa , Antysheva Zoya , Svekolkin Viktor , Tikhonova Ekaterina , Miheecheva Natalia , Kuzkina Natalia , Nos Grigorii , Tabbo Fabrizio , Frenkel Felix , Ghione Paola , Tsiper Maria , Almog Nava , Fowler Nathan , Melnick Ari M. , Leonard John P. , Inghirami Giorgio , Cerchietti Leandro
Published: April 2023

Abstract
Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease. Transcriptomic and genetic characterization of DLBCL has increased the understanding of its intrinsic pathogenesis and provided potential therapeutic targets. However, the role of the microenvironment in DLBCL biology remains less understood. Here, we performed a transcriptomic analysis of the microenvironment of 4,655 DLBCLs from multiple independent cohorts and described four major lymphoma microenvironment categories that associate with distinct biological aberrations and clinical behavior. We also found evidence of genetic and epigenetic mechanisms deployed by cancer cells to evade microenvironmental constraints of lymphoma growth, supporting the rationale for implementing DNA hypomethylating agents in selected patients with DLBCL. In addition, our work uncovered new therapeutic vulnerabilities in the biochemical composition of the extracellular matrix that were exploited to decrease DLBCL proliferation in preclinical models. This novel classification provides a road map for the biological characterization and therapeutic exploitation of the DLBCL microenvironment.
Significance:
In a translational relevant transcriptomic-based classification, we characterized the microenvironment as a critical component of the B-cell lymphoma biology and associated it with the DLBCL clinical behavior establishing a novel opportunity for targeting therapies.

This article is highlighted in the In This Issue feature, p. 1307
Data from Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma
Authors: Ribas Antoni , Medina Theresa , Kirkwood John M. , Zakharia Yousef , Gonzalez Rene , Davar Diwakar , Chmielowski Bartosz , Campbell Katie M. , Bao Riyue , Kelley Heather , Morris Aaron , Mauro David , Wooldridge James E. , Luke Jason J. , Weiner George J. , Krieg Arthur M. , Milhem Mohammed M.
Published: April 2023

Abstract
Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti–PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile, and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an IFNγ gene signature following treatment, as well as increased systemic expression of the IFN-inducible chemokine CXCL10.
Significance:
In this phase Ib study in patients with advanced melanoma, intratumoral TLR9 agonist vidutolimod in combination with pembrolizumab had a manageable safety profile and showed promising clinical activity, supporting the further clinical development of vidutolimod to overcome PD-1 blockade resistance through induction of an IFN response.

See related commentary by Sullivan, p. 2960.

This article is highlighted in the In This Issue feature, p. 2945
Data from NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation
Authors: Papachristodoulou Alexandros , Rodriguez-Calero Antonio , Panja Sukanya , Margolskee Elizabeth , Virk Renu K. , Milner Teresa A. , Martina Luis Pina , Kim Jaime Y. , Di Bernardo Matteo , Williams Alanna B. , Maliza Elvis A. , Caputo Joseph M. , Haas Christopher , Wang Vinson , De Castro Guarionex Joel , Wenske Sven , Hibshoosh Hanina , McKiernan James M. , Shen Michael M. , Rubin Mark A. , Mitrofanova Antonina , Dutta Aditya , Abate-Shen Cory
Published: April 2023

Abstract
Mitochondria provide the first line of defense against the tumor-promoting effects of oxidative stress. Here we show that the prostate-specific homeoprotein NKX3.1 suppresses prostate cancer initiation by protecting mitochondria from oxidative stress. Integrating analyses of genetically engineered mouse models, human prostate cancer cells, and human prostate cancer organotypic cultures, we find that, in response to oxidative stress, NKX3.1 is imported to mitochondria via the chaperone protein HSPA9, where it regulates transcription of mitochondrial-encoded electron transport chain (ETC) genes, thereby restoring oxidative phosphorylation and preventing cancer initiation. Germline polymorphisms of NKX3.1 associated with increased cancer risk fail to protect from oxidative stress or suppress tumorigenicity. Low expression levels of NKX3.1 combined with low expression of mitochondrial ETC genes are associated with adverse clinical outcome, whereas high levels of mitochondrial NKX3.1 protein are associated with favorable outcome. This work reveals an extranuclear role for NKX3.1 in suppression of prostate cancer by protecting mitochondrial function.
Significance:
Our findings uncover a nonnuclear function for NKX3.1 that is a key mechanism for suppression of prostate cancer. Analyses of the expression levels and subcellular localization of NKX3.1 in patients at risk of cancer progression may improve risk assessment in a precision prevention paradigm, particularly for men undergoing active surveillance.

See related commentary by Finch and Baena, p. 2132.

This article is highlighted in the In This Issue feature, p. 2113
Data from Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation
Authors: Quintanal-Villalonga Alvaro , Taniguchi Hirokazu , Zhan Yingqian A. , Hasan Maysun M. , Chavan Shweta S. , Meng Fanli , Uddin Fathema , Manoj Parvathy , Donoghue Mark T.A. , Won Helen H. , Chan Joseph M. , Ciampricotti Metamia , Chow Andrew , Offin Michael , Chang Jason C. , Ray-Kirton Jordana , Tischfield Sam E. , Egger Jacklynn , Bhanot Umesh K. , Linkov Irina , Asher Marina , Sinha Sonali , Silber Joachim , Iacobuzio-Donahue Christine A. , Roehrl Michael H. , Hollmann Travis J. , Yu Helena A. , Qiu Juan , de Stanchina Elisa , Baine Marina K. , Rekhtman Natasha , Poirier John T. , Loomis Brian , Koche Richard P. , Rudin Charles M. , Sen Triparna
Published: April 2023

Abstract
Lineage plasticity is implicated in treatment resistance in multiple cancers. In lung adenocarcinomas (LUAD) amenable to targeted therapy, transformation to small cell lung cancer (SCLC) is a recognized resistance mechanism. Defining molecular mechanisms of neuroendocrine (NE) transformation in lung cancer has been limited by a paucity of pre/posttransformation clinical samples. Detailed genomic, epigenomic, transcriptomic, and protein characterization of combined LUAD/SCLC tumors, as well as pre/posttransformation samples, supports that NE transformation is primarily driven by transcriptional reprogramming rather than mutational events. We identify genomic contexts in which NE transformation is favored, including frequent loss of the 3p chromosome arm. We observed enhanced expression of genes involved in the PRC2 complex and PI3K/AKT and NOTCH pathways. Pharmacologic inhibition of the PI3K/AKT pathway delayed tumor growth and NE transformation in an EGFR-mutant patient-derived xenograft model. Our findings define a novel landscape of potential drivers and therapeutic vulnerabilities of NE transformation in lung cancer.
Significance:
The difficulty in collection of transformation samples has precluded the performance of molecular analyses, and thus little is known about the lineage plasticity mechanisms leading to LUAD-to-SCLC transformation. Here, we describe biological pathways dysregulated upon transformation and identify potential predictors and potential therapeutic vulnerabilities of NE transformation in the lung.

See related commentary by Meador and Lovly, p. 2962.

This article is highlighted in the In This Issue feature, p. 2945
Data from PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability
Authors: Pitarresi Jason R. , Norgard Robert J. , Chiarella Anna M. , Suzuki Kensuke , Bakir Basil , Sahu Varun , Li Jinyang , Zhao Jun , Marchand Benoît , Wengyn Maximilian D. , Hsieh Antony , Kim Il-Kyu , Zhang Amy , Sellin Karine , Lee Vivian , Takano Shigetsugu , Miyahara Yoji , Ohtsuka Masayuki , Maitra Anirban , Notta Faiyaz , Kremer Richard , Stanger Ben Z. , Rustgi Anil K.
Published: April 2023

Abstract
Pancreatic cancer metastasis is a leading cause of cancer-related deaths, yet very little is understood regarding the underlying biology. As a result, targeted therapies to inhibit metastasis are lacking. Here, we report that the parathyroid hormone–related protein (PTHrP encoded by PTHLH) is frequently amplified as part of the KRAS amplicon in patients with pancreatic cancer. PTHrP upregulation drives the growth of both primary and metastatic tumors in mice and is highly enriched in pancreatic ductal adenocarcinoma metastases. Loss of PTHrP—either genetically or pharmacologically—dramatically reduces tumor burden, eliminates metastasis, and enhances overall survival. These effects are mediated in part through a reduction in epithelial-to-mesenchymal transition, which reduces the ability of tumor cells to initiate metastatic cascade. Spp1, which encodes osteopontin, is revealed to be a downstream effector of PTHrP. Our results establish a new paradigm in pancreatic cancer whereby PTHrP is a driver of disease progression and emerges as a novel therapeutic vulnerability.
Significance:
Pancreatic cancer often presents with metastases, yet no strategies exist to pharmacologically inhibit this process. Herein, we establish the oncogenic and prometastatic roles of PTHLH, a novel amplified gene in pancreatic ductal adenocarcinoma. We demonstrate that blocking PTHrP activity reduces primary tumor growth, prevents metastasis, and prolongs survival in mice.

This article is highlighted in the In This Issue feature, p. 1601
Data from The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals
Authors: Fahrner Jean-Eudes , Lahmar Imran , Goubet Anne-Gaëlle , Haddad Yacine , Carrier Agathe , Mazzenga Marine , Drubay Damien , Alves Costa Silva Carolina , de Sousa Eric , Thelemaque Cassandra , Melenotte Cléa , Dubuisson Agathe , Geraud Arthur , Ferrere Gladys , Birebent Roxanne , Bigenwald Camille , Picard Marion , Cerbone Luigi , Lérias Joana R. , Laparra Ariane , Bernard-Tessier Alice , Kloeckner Benoît , Gazzano Marianne , Danlos François-Xavier , Terrisse Safae , Pizzato Eugenie , Flament Caroline , Ly Pierre , Tartour Eric , Benhamouda Nadine , Meziani Lydia , Ahmed-Belkacem Abdelhakim , Miyara Makoto , Gorochov Guy , Barlesi Fabrice , Trubert Alexandre , Ungar Benjamin , Estrada Yeriel , Pradon Caroline , Gallois Emmanuelle , Pommeret Fanny , Colomba Emeline , Lavaud Pernelle , Deloger Marc , Droin Nathalie , Deutsch Eric , Gachot Bertrand , Spano Jean-Philippe , Merad Mansouria , Scotté Florian , Marabelle Aurélien , Griscelli Frank , Blay Jean-Yves , Soria Jean-Charles , Merad Miriam , André Fabrice , Villemonteix Juliette , Chevalier Mathieu F. , Caillat-Zucman Sophie , Fenollar Florence , Guttman-Yassky Emma , Launay Odile , Kroemer Guido , La Scola Bernard , Maeurer Markus , Derosa Lisa , Zitvogel Laurence
Published: April 2023

Abstract
Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants.
Significance:
This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike.

See related commentary by McGary and Vardhana, p. 892.

This article is highlighted in the In This Issue feature, p. 873
Data from Pharmacologic Reduction of Mitochondrial Iron Triggers a Noncanonical BAX/BAK-Dependent Cell Death
Authors: Garciaz Sylvain , Guirguis Andrew A. , Müller Sebastian , Brown Fiona C. , Chan Yih-Chih , Motazedian Ali , Rowe Caitlin L. , Kuzich James A. , Chan Kah Lok , Tran Kevin , Smith Lorey , MacPherson Laura , Liddicoat Brian , Lam Enid Y.N. , Cañeque Tatiana , Burr Marian L. , Litalien Véronique , Pomilio Giovanna , Poplineau Mathilde , Duprez Estelle , Dawson Sarah-Jane , Ramm Georg , Cox Andrew G. , Brown Kristin K. , Huang David C.S. , Wei Andrew H. , McArthur Kate , Rodriguez Raphaël , Dawson Mark A.
Published: April 2023

Abstract
Cancer cell metabolism is increasingly recognized as providing an exciting therapeutic opportunity. However, a drug that directly couples targeting of a metabolic dependency with the induction of cell death in cancer cells has largely remained elusive. Here we report that the drug-like small-molecule ironomycin reduces the mitochondrial iron load, resulting in the potent disruption of mitochondrial metabolism. Ironomycin promotes the recruitment and activation of BAX/BAK, but the resulting mitochondrial outer membrane permeabilization (MOMP) does not lead to potent activation of the apoptotic caspases, nor is the ensuing cell death prevented by inhibiting the previously established pathways of programmed cell death. Consistent with the fact that ironomycin and BH3 mimetics induce MOMP through independent nonredundant pathways, we find that ironomycin exhibits marked in vitro and in vivo synergy with venetoclax and overcomes venetoclax resistance in primary patient samples.
Significance:
Ironomycin couples targeting of cellular metabolism with cell death by reducing mitochondrial iron, resulting in the alteration of mitochondrial metabolism and the activation of BAX/BAK. Ironomycin induces MOMP through a different mechanism to BH3 mimetics, and consequently combination therapy has marked synergy in cancers such as acute myeloid leukemia.

This article is highlighted in the In This Issue feature, p. 587
Data from Science-Driven Nutritional Interventions for the Prevention and Treatment of Cancer
Authors: Montégut Léa , de Cabo Rafael , Zitvogel Laurence , Kroemer Guido
Published: April 2023

Abstract
In population studies, dietary patterns clearly influence the development, progression, and therapeutic response of cancers. Nonetheless, interventional dietary trials have had relatively little impact on the prevention and treatment of malignant disease. Standardization of nutritional interventions combined with high-level mode-of-action studies holds the promise of identifying specific entities and pathways endowed with antineoplastic properties. Here, we critically review the effects of caloric restriction and more specific interventions on macro- and micronutrients in preclinical models as well as in clinical studies. We place special emphasis on the prospect of using defined nutrition-relevant molecules to enhance the efficacy of established anticancer treatments.
Significance:
The avoidance of intrinsically hypercaloric and toxic diets contributes to the prevention and cure of cancer. In addition, specific diet-induced molecules such as ketone bodies and micronutrients, including specific vitamins, have drug-like effects that are clearly demonstrable in preclinical models, mostly in the context of immunotherapies. Multiple trials are underway to determine the clinical utility of such molecules.
Data from Identification of Functional Heterogeneity of Carcinoma-Associated Fibroblasts with Distinct IL6-Mediated Therapy Resistance in Pancreatic Cancer
Authors: McAndrews Kathleen M. , Chen Yang , Darpolor J. Kebbeh , Zheng Xiaofeng , Yang Sujuan , Carstens Julienne L. , Li Bingrui , Wang Huamin , Miyake Toru , Correa de Sampaio Pedro , Kirtley Michelle L. , Natale Mariangela , Wu Chia-Chin , Sugimoto Hikaru , LeBleu Valerie S. , Kalluri Raghu
Published: April 2023

Abstract
The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) involves a significant accumulation of fibroblasts as part of the host response to cancer. Using single-cell RNA sequencing, multiplex immunostaining, and several genetic mouse models, we identify carcinoma-associated fibroblasts (CAF) with opposing functions in PDAC progression. Depletion of fibroblast activation protein (FAP)+ CAFs results in increased survival, in contrast to depletion of alpha smooth muscle actin (αSMA)+ CAFs, which leads to decreased survival. Tumor-promoting FAP+ CAFs (TP-CAF) and tumor-restraining αSMA+ CAFs (TR-CAF) differentially regulate cancer-associated pathways and accumulation of regulatory T cells. Improved efficacy of gemcitabine is observed when IL6 is deleted from αSMA+ CAFs but not from FAP+ CAFs using dual-recombinase genetic PDAC models. Improved gemcitabine efficacy due to lack of IL6 synergizes with anti–PD-1 immunotherapy to significantly improve survival of PDAC mice. Our study identifies functional heterogeneity of CAFs in PDAC progression and their different roles in therapy response.
Significance:
PDAC is associated with accumulation of dense stroma consisting of fibroblasts and extracellular matrix that regulate tumor progression. Here, we identify two distinct populations of fibroblasts with opposing roles in the progression and immune landscape of PDAC. Our findings demonstrate that fibroblasts are functionally diverse with therapeutic implications.

This article is highlighted in the In This Issue feature, p. 1397
Data from Genomic Landscape and Clinical Utility in Korean Advanced Pan-Cancer Patients from Prospective Clinical Sequencing: K-MASTER Program
Authors: Park Kyong Hwa , Choi Jung Yoon , Lim Ah-Reum , Kim Ju Won , Choi Yoon Ji , Lee Soohyeon , Sung Jae Sook , Chung Hee-Joon , Jang Byunghyun , Yoon Dayoung , Kim Sukwon , Sa Jason K. , Kim Yeul Hong
Published: April 2023

Abstract
The fundamental principle of precision oncology is centralized on the identification of therapeutically exploitable targets that provides individual patients with cancer an opportunity to make informed decisions on a personalized level. To facilitate and adopt such concepts within clinical practice, we have initiated a nationwide, multi-institutional precision oncology screening program to examine and enroll patients into the most appropriate clinical trial based on their tumor's unique molecular properties. To determine the prevalence of essential major driver mutations and to explore their dynamic associations at both molecular and pathway levels, we present a comprehensive overview on the genomic properties of East Asian patients with cancer. We further delineate the extent of genomic diversity as well as clinical actionability in patients from Western and Eastern cultures at the pan-cancer and single-tumor entity levels. To support fellow oncology communities in future investigations involving large-scale analysis, all data have been made accessible to the public (https://kmportal.or.kr).
Significance:
We present a comprehensive overview of molecular properties of East Asian pan-cancer patients and demonstrate significant diversity in terms of genomic characteristics as well as clinical utility compared with patients with European ancestry. The results of this study will lay the groundwork for designing personalized treatments in the clinical setting.

See related commentary by Moyers and Subbiah, p. 886.

This article is highlighted in the In This Issue feature, p. 873
Data from The European MAPPYACTS Trial: Precision Medicine Program in Pediatric and Adolescent Patients with Recurrent Malignancies
Authors: Berlanga Pablo , Pierron Gaelle , Lacroix Ludovic , Chicard Mathieu , Adam de Beaumais Tiphaine , Marchais Antonin , Harttrampf Anne C. , Iddir Yasmine , Larive Alicia , Soriano Fernandez Aroa , Hezam Imene , Chevassus Cecile , Bernard Virginie , Cotteret Sophie , Scoazec Jean-Yves , Gauthier Arnaud , Abbou Samuel , Corradini Nadege , André Nicolas , Aerts Isabelle , Thebaud Estelle , Casanova Michela , Owens Cormac , Hladun-Alvaro Raquel , Michiels Stefan , Delattre Olivier , Vassal Gilles , Schleiermacher Gudrun , Geoerger Birgit
Published: April 2023

Abstract
MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one genetic alteration leading to a targeted treatment suggestion was identified in 436 patients (69%) with successful sequencing; 10% of these alterations were considered “ready for routine use.” Of 356 patients with follow-up beyond 12 months, 107 (30%) received one or more matched targeted therapies—56% of them within early clinical trials—mainly in the AcSé-ESMART platform trial (NCT02813135). Overall, matched treatment resulted in a 17% objective response rate, and of those patients with ready for routine use alterations, it was 38%. In patients with extracerebral tumors, 76% of actionable alterations detected in tumor tissue were also identified in circulating cell-free DNA (cfDNA).
Significance:
MAPPYACTS underlines the feasibility of molecular profiling at cancer recurrence in children on a multicenter, international level and demonstrates benefit for patients with selected key drivers. The use of cfDNA deserves validation in prospective studies. Our study highlights the need for innovative therapeutic proof-of-concept trials that address the underlying cancer complexity.

This article is highlighted in the In This Issue feature, p. 1171