bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Impact of HER2 Heterogeneity on Treatment Response of Early-Stage HER2-Positive Breast Cancer: Phase II Neoadjuvant Clinical Trial of T-DM1 Combined with Pertuzumab
Authors: Filho Otto Metzger , Viale Giuseppe , Stein Shayna , Trippa Lorenzo , Yardley Denise A. , Mayer Ingrid A. , Abramson Vandana G. , Arteaga Carlos L. , Spring Laura M. , Waks Adrienne G. , Wrabel Eileen , DeMeo Michelle K. , Bardia Aditya , Dell'Orto Patrizia , Russo Leila , King Tari A. , Polyak Kornelia , Michor Franziska , Winer Eric P. , Krop Ian E.
Published: April 2023

Abstract
Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 (ERBB2) heterogeneity on response to HER2-targeted therapy, we treated 164 patients with centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from two locations of each tumor. HER2 heterogeneity, defined as an area with ERBB2 amplification in >5% but <50% of tumor cells, or a HER2-negative area by FISH, was detected in 10% (16/157) of evaluable cases. The pathologic complete response rate was 55% in the nonheterogeneous subgroup and 0% in the heterogeneous group (P < 0.0001, adjusted for hormone receptor status). Single-cell ERBB2 FISH analysis of cellular heterogeneity identified the fraction of ERBB2 nonamplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies.
Significance:
HER2-targeted therapies improve cure rates in HER2-positive breast cancer, suggesting chemotherapy can be avoided in a subset of patients. We show that HER2 heterogeneity, particularly the fraction of ERBB2 nonamplified cancer cells, is a strong predictor of resistance to HER2 therapies and could potentially be used to optimize treatment selection.

See related commentary by Okines and Turner, p. 2369.

This article is highlighted in the In This Issue feature, p. 2355
Data from Surface Proteomics Reveals CD72 as a Target for In Vitro–Evolved Nanobody-Based CAR-T Cells in KMT2A/MLL1-Rearranged B-ALL
Authors: Nix Matthew A. , Mandal Kamal , Geng Huimin , Paranjape Neha , Lin Yu-Hsiu T. , Rivera Jose M. , Marcoulis Makeba , White Kristie L. , Whitman Jeffrey D. , Bapat Sagar P. , Parker Kevin R. , Ramirez Jonathan , Deucher Anne , Phojanokong Paul , Steri Veronica , Fattahi Faranak , Hann Byron C. , Satpathy Ansuman T. , Manglik Aashish , Stieglitz Elliot , Wiita Arun P.
Published: April 2023

Abstract
Alternative strategies are needed for patients with B-cell malignancy relapsing after CD19-targeted immunotherapy. Here, cell surface proteomics revealed CD72 as an optimal target for poor-prognosis KMT2A/MLL1-rearranged (MLLr) B-cell acute lymphoblastic leukemia (B-ALL), which we further found to be expressed in other B-cell malignancies. Using a recently described, fully in vitro system, we selected synthetic CD72-specific nanobodies, incorporated them into chimeric antigen receptors (CAR), and demonstrated robust activity against B-cell malignancy models, including CD19 loss. Taking advantage of the role of CD72 in inhibiting B-cell receptor signaling, we found that SHIP1 inhibition increased CD72 surface density. We establish that CD72-nanobody CAR-T cells are a promising therapy for MLLr B-ALL.
Significance:
Patients with MLLr B-ALL have poor prognoses despite recent immunotherapy advances. Here, surface proteomics identifies CD72 as being enriched on MLLr B-ALL but also widely expressed across B-cell cancers. We show that a recently described, fully in vitro nanobody platform generates binders highly active in CAR-T cells and demonstrate its broad applicability for immunotherapy development.

This article is highlighted in the In This Issue feature, p. 1861
Data from Six-Month Efficacy and Toxicity Profile of BNT162b2 Vaccine in Cancer Patients with Solid Tumors
Authors: Waldhorn Ithai , Holland Roy , Goshen-Lago Tal , Shirman Yelena , Szwarcwort-Cohen Moran , Reiner-Benaim Anat , Shachor-Meyouhas Yael , Hussein Khetam , Fahoum Liana , Peer Avivit , Almog Ronit , Shaked Yuval , Halberthal Michael , Ben-Aharon Irit
Published: April 2023

Abstract
We had previously reported short-term efficacy, immunogenicity, and safety of the BNT162b2 vaccine among cancer patients with solid tumors. We aimed to evaluate these outcomes at six months postvaccination. The study cohort comprised patients who were on treatment during vaccination and throughout six months postvaccination. Serologic tests were performed after second vaccination and six months afterward. An age-matched cohort of health care workers served as controls. Documentation of COVID-19 infection, blood tests, and imaging studies during the study period was reviewed. Participants included 154 patients and 135 controls. Six months postvaccination, 122 (79%) patients were seropositive compared with 114 (84%) controls (P = 0.32). Serology titer dramatically decreased in a similar manner in both cohorts. No COVID-19 cases were documented in controls, and one case occurred in patient cohort. All previously reported adverse effects resolved. Taken together, the pattern of immunogenicity, efficacy, and safety of BNT162b2 in patients with cancer with solid tumors at six months postvaccination resembles that of the general population.
Significance:
Evidence regarding efficacy and safety of COVID-19 vaccines in patients with cancer indicate a favorable short-term profile. Immunomodulation due to anticancer treatments may affect immunity and immunogenicity of patients with cancer to the BNT162b2 vaccine over time. Our study sheds light on these long-term outcomes and portrays a trend that resembles the general population.

This article is highlighted in the In This Issue feature, p. 2355
Data from Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer
Authors: Coates James T. , Sun Sheng , Leshchiner Ignaty , Thimmiah Nayana , Martin Elizabeth E. , McLoughlin Daniel , Danysh Brian P. , Slowik Kara , Jacobs Raquel A. , Rhrissorrakrai Kahn , Utro Filippo , Levovitz Chaya , Denault Elyssa , Walmsley Charlotte S. , Kambadakone Avinash , Stone James R. , Isakoff Steven J. , Parida Laxmi , Juric Dejan , Getz Gad , Bardia Aditya , Ellisen Leif W.
Published: April 2023

Abstract
Sacituzumab govitecan (SG), the first antibody–drug conjugate (ADC) approved for triple-negative breast cancer, incorporates the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) inhibitor payload. We sought to identify mechanisms of SG resistance through RNA and whole-exome sequencing of pretreatment and postprogression specimens. One patient exhibiting de novo progression lacked TROP2 expression, in contrast to robust TROP2 expression and focal genomic amplification of TACSTD2/TROP2 observed in a patient with a deep, prolonged response to SG. Analysis of acquired genomic resistance in this case revealed one phylogenetic branch harboring a canonical TOP1E418K resistance mutation and subsequent frameshift TOP1 mutation, whereas a distinct branch exhibited a novel TACSTD2/TROP2T256R missense mutation. Reconstitution experiments demonstrated that TROP2T256R confers SG resistance via defective plasma membrane localization and reduced cell-surface binding by hRS7. These findings highlight parallel genomic alterations in both antibody and payload targets associated with resistance to SG.
Significance:
These findings underscore TROP2 as a response determinant and reveal acquired SG resistance mechanisms involving the direct antibody and drug payload targets in distinct metastatic subclones of an individual patient. This study highlights the specificity of SG and illustrates how such mechanisms will inform therapeutic strategies to overcome ADC resistance.

This article is highlighted in the In This Issue feature, p. 2355
Data from Reducing Skin Toxicities from EGFR Inhibitors with Topical BRAF Inhibitor Therapy
Authors: Lacouture Mario E. , Wainberg Zev A. , Patel Anisha B. , Anadkat Milan J. , Stemmer Salomon M. , Shacham-Shmueli Einat , Medina Egmidio , Zelinger Galit , Shelach Noa , Ribas Antoni
Published: April 2023

Abstract
Treatment of cancer with EGFR inhibitors is limited by on-target skin toxicities induced by inhibition of the MAPK pathway. BRAF inhibitors are known to paradoxically activate the MAPK downstream of EGFR, which we confirmed using human skin keratinocytes. We then conducted a phase I clinical trial testing the hypothesis that topical therapy with the BRAF inhibitor LUT014 could improve skin toxicities induced by EGFR inhibitors. Ten patients with metastatic colorectal cancer who had developed acneiform rash while being treated with cetuximab or panitumumab were enrolled in three cohorts. LUT014 was well tolerated, and there were no dose-limiting toxicities. The acneiform rash improved in the 6 patients who started with grade 2 rash in the low and intermediate cohorts. We conclude that topical LUT014 is safe and efficacious in improving rash from EGFR inhibitors, consistent with the mechanism of action inducting paradoxical MAPK activation.
Significance:
BRAF inhibitor topical therapy could avoid dose reductions of EGFR inhibitors, locally treating the main dose-limiting skin toxicity of this class of agents.

This article is highlighted in the In This Issue feature, p. 2113
Data from Werner Helicase Is a Synthetic-Lethal Vulnerability in Mismatch Repair–Deficient Colorectal Cancer Refractory to Targeted Therapies, Chemotherapy, and Immunotherapy
Authors: Picco Gabriele , Cattaneo Chiara M. , van Vliet Esmée J. , Crisafulli Giovanni , Rospo Giuseppe , Consonni Sarah , Vieira Sara F. , Rodríguez Iñigo Sánchez , Cancelliere Carlotta , Banerjee Ruby , Schipper Luuk J. , Oddo Daniele , Dijkstra Krijn K. , Cinatl Jindrich , Michaelis Martin , Yang Fengtang , Di Nicolantonio Federica , Sartore-Bianchi Andrea , Siena Salvatore , Arena Sabrina , Voest Emile E. , Bardelli Alberto , Garnett Mathew J.
Published: April 2023

Abstract
Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair–deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer. The clinical effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of patients receiving immunotherapy have disease that is refractory to immune checkpoint inhibitors. Loss of Werner syndrome ATP-dependent helicase (WRN) is a synthetic lethality in dMMR/MSI-H cells. To inform the development of WRN as a therapeutic target, we performed WRN knockout or knockdown in 60 heterogeneous dMMR colorectal cancer preclinical models, demonstrating that WRN dependency is an almost universal feature and a robust marker for patient selection. Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency. These data show the potential of therapeutically targeting WRN in patients with dMMR/MSI-H colorectal cancer and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies.
Significance:
We found that a large, diverse set of dMMR/MSI-H colorectal cancer preclinical models, including models of treatment-refractory disease, are WRN-dependent. Our results support WRN as a promising synthetic-lethal target in dMMR/MSI-H colorectal cancer tumors as a monotherapy or in combination with targeted agents, chemotherapy, or immunotherapy.

This article is highlighted in the In This Issue feature, p. 1861
Data from Clinical Acquired Resistance to KRASG12C Inhibition through a Novel KRAS Switch-II Pocket Mutation and Polyclonal Alterations Converging on RAS–MAPK Reactivation
Authors: Tanaka Noritaka , Lin Jessica J. , Li Chendi , Ryan Meagan B. , Zhang Junbing , Kiedrowski Lesli A. , Michel Alexa G. , Syed Mohammed U. , Fella Katerina A. , Sakhi Mustafa , Baiev Islam , Juric Dejan , Gainor Justin F. , Klempner Samuel J. , Lennerz Jochen K. , Siravegna Giulia , Bar-Peled Liron , Hata Aaron N. , Heist Rebecca S. , Corcoran Ryan B.
Published: April 2023

Abstract
Mutant-selective KRASG12C inhibitors, such as MRTX849 (adagrasib) and AMG 510 (sotorasib), have demonstrated efficacy in KRASG12C-mutant cancers, including non–small cell lung cancer (NSCLC). However, mechanisms underlying clinical acquired resistance to KRASG12C inhibitors remain undetermined. To begin to define the mechanistic spectrum of acquired resistance, we describe a patient with KRASG12C NSCLC who developed polyclonal acquired resistance to MRTX849 with the emergence of 10 heterogeneous resistance alterations in serial cell-free DNA spanning four genes (KRAS, NRAS, BRAF, MAP2K1), all of which converge to reactivate RAS–MAPK signaling. Notably, a novel KRASY96D mutation affecting the switch-II pocket, to which MRTX849 and other inactive-state inhibitors bind, was identified that interferes with key protein–drug interactions and confers resistance to these inhibitors in engineered and patient-derived KRASG12C cancer models. Interestingly, a novel, functionally distinct tricomplex KRASG12C active-state inhibitor RM-018 retained the ability to bind and inhibit KRASG12C/Y96D and could overcome resistance.
Significance:
In one of the first reports of clinical acquired resistance to KRASG12C inhibitors, our data suggest polyclonal RAS–MAPK reactivation as a central resistance mechanism. We also identify a novel KRAS switch-II pocket mutation that impairs binding and drives resistance to inactive-state inhibitors but is surmountable by a functionally distinct KRASG12C inhibitor.

See related commentary by Pinnelli and Trusolino, p. 1874.

This article is highlighted in the In This Issue feature, p. 1861
Data from Obesity-Dependent Adipokine Chemerin Suppresses Fatty Acid Oxidation to Confer Ferroptosis Resistance
Authors: Tan Sze Kiat , Mahmud Iqbal , Fontanesi Flavia , Puchowicz Michelle , Neumann Chase K.A. , Griswold Anthony J. , Patel Rutulkumar , Dispagna Marco , Ahmed Hamzah H. , Gonzalgo Mark L. , Brown J. Mark , Garrett Timothy J. , Welford Scott M.
Published: April 2023

Abstract
Clear cell renal cell carcinoma (ccRCC) is characterized by accumulation of neutral lipids and adipogenic transdifferentiation. We assessed adipokine expression in ccRCC and found that tumor tissues and patient plasma exhibit obesity-dependent elevations of the adipokine chemerin. Attenuation of chemerin by several approaches led to significant reduction in lipid deposition and impairment of tumor cell growth in vitro and in vivo. A multi-omics approach revealed that chemerin suppresses fatty acid oxidation, preventing ferroptosis, and maintains fatty acid levels that activate hypoxia-inducible factor 2α expression. The lipid coenzyme Q and mitochondrial complex IV, whose biogeneses are lipid-dependent, were found to be decreased after chemerin inhibition, contributing to lipid reactive oxygen species production. Monoclonal antibody targeting chemerin led to reduced lipid storage and diminished tumor growth, demonstrating translational potential of chemerin inhibition. Collectively, the results suggest that obesity and tumor cells contribute to ccRCC through the expression of chemerin, which is indispensable in ccRCC biology.
Significance:
Identification of a hypoxia-inducible factor–dependent adipokine that prevents fatty acid oxidation and causes escape from ferroptosis highlights a critical metabolic dependency unique in the clear cell subtype of kidney cancer. Targeting lipid metabolism via inhibition of a soluble factor is a promising pharmacologic approach to expand therapeutic strategies for patients with ccRCC.

See related commentary by Reznik et al., p. 1879.

This article is highlighted in the In This Issue feature, p. 1861
Data from CDK4/6 Inhibition Promotes Antitumor Immunity through the Induction of T-cell Memory
Authors: Lelliott Emily J. , Kong Isabella Y. , Zethoven Magnus , Ramsbottom Kelly M. , Martelotto Luciano G. , Meyran Deborah , Zhu Joe Jiang , Costacurta Matteo , Kirby Laura , Sandow Jarrod J. , Lim Lydia , Dominguez Pilar M. , Todorovski Izabela , Haynes Nicole M. , Beavis Paul A. , Neeson Paul J. , Hawkins Edwin D. , McArthur Grant A. , Parish Ian A. , Johnstone Ricky W. , Oliaro Jane , Sheppard Karen E. , Kearney Conor J. , Vervoort Stephin J.
Published: April 2023

Abstract
Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) are an approved treatment for hormone receptor–positive breast cancer and are currently under evaluation across hundreds of clinical trials for other cancer types. The clinical success of these inhibitors is largely attributed to well-defined tumor-intrinsic cytostatic mechanisms, whereas their emerging role as immunomodulatory agents is less understood. Using integrated epigenomic, transcriptomic, and proteomic analyses, we demonstrated a novel action of CDK4/6 inhibitors in promoting the phenotypic and functional acquisition of immunologic T-cell memory. Short-term priming with a CDK4/6 inhibitor promoted long-term endogenous antitumor T-cell immunity in mice, enhanced the persistence and therapeutic efficacy of chimeric antigen receptor T cells, and induced a retinoblastoma-dependent T-cell phenotype supportive of favorable responses to immune checkpoint blockade in patients with melanoma. Together, these mechanistic insights significantly broaden the prospective utility of CDK4/6 inhibitors as clinical tools to boost antitumor T-cell immunity.
Significance:
Immunologic memory is critical for sustained antitumor immunity. Our discovery that CDK4/6 inhibitors drive T-cell memory fate commitment sheds new light on their clinical activity, which is essential for the design of clinical trial protocols incorporating these agents, particularly in combination with immunotherapy, for the treatment of cancer.

This article is highlighted in the In This Issue feature, p. 2355
Data from Futibatinib, an Irreversible FGFR1–4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study
Authors: Meric-Bernstam Funda , Bahleda Rastislav , Hierro Cinta , Sanson Marc , Bridgewater John , Arkenau Hendrik-Tobias , Tran Ben , Kelley Robin Kate , Park Joon Oh , Javle Milind , He Yaohua , Benhadji Karim A. , Goyal Lipika
Published: April 2023

Abstract
Futibatinib, a highly selective, irreversible FGFR1–4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1–3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement–positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy.
Significance:
This phase I dose-expansion trial demonstrated clinical activity and tolerability of the irreversible FGFR1–4 inhibitor futibatinib across a broad spectrum of FGFR-aberrant tumors. These results formed the rationale for ongoing phase II/III futibatinib trials in cholangiocarcinoma, breast cancer, gastroesophageal cancer, and a genomically selected disease-agnostic population.

This article is highlighted in the In This Issue feature, p. 275
Data from Endogenous Retroelement Activation by Epigenetic Therapy Reverses the Warburg Effect and Elicits Mitochondrial-Mediated Cancer Cell Death
Authors: Fresquet Vicente , Garcia-Barchino Maria J. , Larrayoz Marta , Celay Jon , Vicente Carmen , Fernandez-Galilea Marta , Larrayoz Maria J. , Calasanz Maria J. , Panizo Carlos , Junza Alexandra , Han Jiahuai , Prior Celia , Fortes Puri , Pio Ruben , Oyarzabal Julen , Martinez-Baztan Alvaro , Paiva Bruno , Moreno-Aliaga Maria J. , Odero Maria D. , Agirre Xabier , Yanes Oscar , Prosper Felipe , Martinez-Climent Jose A.
Published: April 2023

Abstract
For millions of years, endogenous retroelements have remained transcriptionally silent within mammalian genomes by epigenetic mechanisms. Modern anticancer therapies targeting the epigenetic machinery awaken retroelement expression, inducing antiviral responses that eliminate tumors through mechanisms not completely understood. Here, we find that massive binding of epigenetically activated retroelements by RIG-I and MDA5 viral sensors promotes ATP hydrolysis and depletes intracellular energy, driving tumor killing independently of immune signaling. Energy depletion boosts compensatory ATP production by switching glycolysis to mitochondrial oxidative phosphorylation, thereby reversing the Warburg effect. However, hyperfunctional succinate dehydrogenase in mitochondrial electron transport chain generates excessive oxidative stress that unleashes RIP1-mediated necroptosis. To maintain ATP generation, hyperactive mitochondrial membrane blocks intrinsic apoptosis by increasing BCL2 dependency. Accordingly, drugs targeting BCL2 family proteins and epigenetic inhibitors yield synergistic responses in multiple cancer types. Thus, epigenetic therapy kills cancer cells by rewiring mitochondrial metabolism upon retroelement activation, which primes mitochondria to apoptosis by BH3-mimetics.
Significance:
The state of viral mimicry induced by epigenetic therapies in cancer cells remodels mitochondrial metabolism and drives caspase-independent tumor cell death, which sensitizes to BCL2 inhibitor drugs. This novel mechanism underlies clinical efficacy of hypomethylating agents and venetoclax in acute myeloid leukemia, suggesting similar combination therapies for other incurable cancers.

This article is highlighted in the In This Issue feature, p. 995
Data from A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS–Driven Lung Cancer
Authors: Cai Hongchen , Chew Su Kit , Li Chuan , Tsai Min K. , Andrejka Laura , Murray Christopher W. , Hughes Nicholas W. , Shuldiner Emily G. , Ashkin Emily L. , Tang Rui , Hung King L. , Chen Leo C. , Lee Shi Ya C. , Yousefi Maryam , Lin Wen-Yang , Kunder Christian A. , Cong Le , McFarland Christopher D. , Petrov Dmitri A. , Swanton Charles , Winslow Monte M.
Published: April 2023

Abstract
Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS–driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression.
Significance:
Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS–driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative in vivo genetic analyses in autochthonous cancer models.

This article is highlighted in the In This Issue feature, p. 1601
Data from Blocking Short-Form Ron Eliminates Breast Cancer Metastases through Accumulation of Stem-Like CD4+ T Cells That Subvert Immunosuppression
Authors: Lai Shu-Chin Alicia , Gundlapalli Harika , Ekiz H. Atakan , Jiang Amanda , Fernandez Elvelyn , Welm Alana L.
Published: April 2023

Abstract
Immunotherapy has potential to prevent and treat metastatic breast cancer, but strategies to enhance immune-mediated killing of metastatic tumors are urgently needed. We report that a ligand-independent isoform of Ron kinase (SF-Ron) is a key target to enhance immune infiltration and eradicate metastatic tumors. Host-specific deletion of SF-Ron caused recruitment of lymphocytes to micrometastases, augmented tumor-specific T-cell responses, and nearly eliminated breast cancer metastasis in mice. Lack of host SF-Ron caused stem-like TCF1+ CD4+ T cells with type I differentiation potential to accumulate in metastases and prevent metastatic outgrowth. There was a corresponding increase in tumor-specific CD8+ T cells, which were also required to eliminate lung metastases. Treatment of mice with a Ron kinase inhibitor increased tumor-specific CD8+ T cells and protected from metastatic outgrowth. These data provide a strong preclinical rationale to pursue small-molecule Ron kinase inhibitors for the prevention and treatment of metastatic breast cancer.
Significance:
The discovery that SF-Ron promotes antitumor immune responses has significant clinical implications. Therapeutic antibodies targeting full-length Ron may not be effective for immunotherapy; poor efficacy of such antibodies in trials may be due to their inability to block SF-Ron. Our data warrant trials with inhibitors targeting SF-Ron in combination with immunotherapy.

This article is highlighted in the In This Issue feature, p. 2945
Data from Macropinocytosis in Cancer-Associated Fibroblasts Is Dependent on CaMKK2/ARHGEF2 Signaling and Functions to Support Tumor and Stromal Cell Fitness
Authors: Zhang Yijuan , Recouvreux M. Victoria , Jung Michael , Galenkamp Koen M.O. , Li Yunbo , Zagnitko Olga , Scott David A. , Lowy Andrew M. , Commisso Cosimo
Published: April 2023

Abstract
Although pancreatic ductal adenocarcinoma (PDAC) cells are exposed to a nutrient-depleted tumor microenvironment, they can acquire nutrients via macropinocytosis, an endocytic form of protein scavenging that functions to support cancer metabolism. Here, we provide evidence that macropinocytosis is also operational in the pancreatic tumor stroma. We find that glutamine deficiency triggers macropinocytic uptake in pancreatic cancer–associated fibroblasts (CAF). Mechanistically, we decipher that stromal macropinocytosis is potentiated via the enhancement of cytosolic Ca2+ and dependent on ARHGEF2 and CaMKK2-AMPK signaling. We elucidate that macropinocytosis has a dual function in CAFs—it serves as a source of intracellular amino acids that sustain CAF cell fitness and function, and it provides secreted amino acids that promote tumor cell survival. Importantly, we demonstrate that stromal macropinocytosis supports PDAC tumor growth. These results highlight the functional role of macropinocytosis in the tumor stroma and provide a mechanistic understanding of how nutrient deficiency can control stromal protein scavenging.
Significance:
Glutamine deprivation drives stromal macropinocytosis to support CAF cell fitness and provide amino acids that sustain PDAC cell survival. Selective disruption of macropinocytosis in CAFs suppresses PDAC tumor growth.

This article is highlighted in the In This Issue feature, p. 1601
Data from A Chimeric GM-CSF/IL18 Receptor to Sustain CAR T-cell Function
Authors: Lange Shannon , Sand Laurens G.L. , Bell Matthew , Patil Sagar L. , Langfitt Deanna , Gottschalk Stephen
Published: April 2023

Abstract
The inability of chimeric antigen receptor (CAR) T cells to sustain their effector function after repeated exposure to tumor cells is a major obstacle to their success in patients with solid tumors. To overcome this limitation, we designed a novel chimeric cytokine receptor to create an autocrine loop that links activation-dependent GM-CSF production by CAR T cells to IL18 receptor signaling (GM18). Expression of GM18 in CAR T cells enhanced their effector function in an antigen- and activation-dependent manner. In repeat stimulation assays, which mimic chronic antigen exposure, CAR.GM18 T cells had a significantly greater ability to expand and produce cytokines in comparison with their unmodified counterparts targeting EPHA2 or HER2. In vivo, CAR.GM18 T cells induced tumor regression at cell doses at which standard CAR T cells were ineffective in two solid tumor xenograft models. Thus, our study highlights the potential of hijacking cytokines that are physiologically secreted by T cells to bolster their antitumor activity.
Significance:
We designed a chimeric cytokine receptor (GM18) that links CAR T-cell activation to MYD88 signaling. GM18 endows CAR T cells with sustained effector function in the setting of chronic antigen exposure, resulting in potent antitumor activity in preclinical solid tumor models.

This article is highlighted in the In This Issue feature, p. 1601
Data from A Summary of the Inaugural WHO Classification of Pediatric Tumors: Transitioning from the Optical into the Molecular Era
Authors: Pfister Stefan M. , Reyes-Múgica Miguel , Chan John K.C. , Hasle Henrik , Lazar Alexander J. , Rossi Sabrina , Ferrari Andrea , Jarzembowski Jason A. , Pritchard-Jones Kathy , Hill D. Ashley , Jacques Thomas S. , Wesseling Pieter , López Terrada Dolores H. , von Deimling Andreas , Kratz Christian P. , Cree Ian A. , Alaggio Rita
Published: April 2023

Abstract
Pediatric tumors are uncommon, yet are the leading cause of cancer-related death in childhood. Tumor types, molecular characteristics, and pathogenesis are unique, often originating from a single genetic driver event. The specific diagnostic challenges of childhood tumors led to the development of the first World Health Organization (WHO) Classification of Pediatric Tumors. The classification is rooted in a multilayered approach, incorporating morphology, IHC, and molecular characteristics. The volume is organized according to organ sites and provides a single, state-of-the-art compendium of pediatric tumor types. A special emphasis was placed on “blastomas,” which variably recapitulate the morphologic maturation of organs from which they originate.
Significance:
In this review, we briefly summarize the main features and updates of each chapter of the inaugural WHO Classification of Pediatric Tumors, including its rapid transition from a mostly microscopic into a molecularly driven classification systematically taking recent discoveries in pediatric tumor genomics into account.
Data from PRC2 Inhibitors Overcome Glucocorticoid Resistance Driven by NSD2 Mutation in Pediatric Acute Lymphoblastic Leukemia
Authors: Li Jianping , Hlavka-Zhang Julia , Shrimp Jonathan H. , Piper Crissandra , Dupéré-Richér Daphne , Roth Jacob S. , Jing Duohui , Casellas Román Heidi L. , Troche Catalina , Swaroop Alok , Kulis Marta , Oyer Jon A. , Will Christine M. , Shen Min , Riva Alberto , Bennett Richard L. , Ferrando Adolfo A. , Hall Matthew D. , Lock Richard B. , Licht Jonathan D.
Published: April 2023

Abstract
Mutations in epigenetic regulators are common in relapsed pediatric acute lymphoblastic leukemia (ALL). Here, we uncovered the mechanism underlying the relapse of ALL driven by an activating mutation of the NSD2 histone methyltransferase (p.E1099K). Using high-throughput drug screening, we found that NSD2-mutant cells were specifically resistant to glucocorticoids. Correction of this mutation restored glucocorticoid sensitivity. The transcriptional response to glucocorticoids was blocked in NSD2-mutant cells due to depressed glucocorticoid receptor (GR) levels and the failure of glucocorticoids to autoactivate GR expression. Although H3K27me3 was globally decreased by NSD2 p.E1099K, H3K27me3 accumulated at the NR3C1 (GR) promoter. Pretreatment of NSD2 p.E1099K cell lines and patient-derived xenograft samples with PRC2 inhibitors reversed glucocorticoid resistance in vitro and in vivo. PRC2 inhibitors restored NR3C1 autoactivation by glucocorticoids, increasing GR levels and allowing GR binding and activation of proapoptotic genes. These findings suggest a new therapeutic approach to relapsed ALL associated with NSD2 mutation.
Significance:
NSD2 histone methyltransferase mutations observed in relapsed pediatric ALL drove glucocorticoid resistance by repression of the GR and abrogation of GR gene autoactivation due to accumulation of K3K27me3 at its promoter. Pretreatment with PRC2 inhibitors reversed resistance, suggesting a new therapeutic approach to these patients with ALL.

This article is highlighted in the In This Issue feature, p. 1
Data from Mitochondrial Fragmentation Triggers Ineffective Hematopoiesis in Myelodysplastic Syndromes
Authors: Aoyagi Yasushige , Hayashi Yoshihiro , Harada Yuka , Choi Kwangmin , Matsunuma Natsumi , Sadato Daichi , Maemoto Yuki , Ito Akihiro , Yanagi Shigeru , Starczynowski Daniel T. , Harada Hironori
Published: April 2023

Abstract
Ineffective hematopoiesis is a fundamental process leading to the pathogenesis of myelodysplastic syndromes (MDS). However, the pathobiological mediators of ineffective hematopoiesis in MDS remain unclear. Here, we demonstrated that overwhelming mitochondrial fragmentation in mutant hematopoietic stem cells and progenitors (HSC/P) triggers ineffective hematopoiesis in MDS. Mouse modeling of CBL exon deletion with RUNX1 mutants, previously unreported comutations in patients with MDS, recapitulated not only clinically relevant MDS phenotypes but also a distinct MDS-related gene signature. Mechanistically, dynamin-related protein 1 (DRP1)–dependent excessive mitochondrial fragmentation in HSC/Ps led to excessive reactive oxygen species production, induced inflammatory signaling activation, and promoted subsequent dysplasia formation and impairment of granulopoiesis. Mitochondrial fragmentation was generally observed in patients with MDS. Pharmacologic inhibition of DRP1 attenuated mitochondrial fragmentation and rescued ineffective hematopoiesis phenotypes in mice with MDS. These findings provide mechanistic insights into ineffective hematopoiesis and indicate that dysregulated mitochondrial dynamics could be a therapeutic target for bone marrow failure in MDS.
Significance:
We demonstrated that excessive mitochondrial fragmentation is a fundamental pathobiological phenomenon that could trigger dysplasia formation and ineffective hematopoiesis in MDS. Our findings provide mechanistic insights into ineffective hematopoiesis and suggest dysregulated mitochondrial dynamics as a therapeutic target for treating MDS.

This article is highlighted in the In This Issue feature, p. 1
Data from Efficacy, Safety, and Biomarker Analysis of Combined PD-L1 (Atezolizumab) and VEGF (Bevacizumab) Blockade in Advanced Malignant Peritoneal Mesothelioma
Authors: Raghav Kanwal , Liu Suyu , Overman Michael J. , Willett Anneleis F. , Knafl Mark , Fu Szu-Chin , Malpica Anais , Prasad Seema , Royal Richard E. , Scally Christopher P. , Mansfield Paul F. , Wistuba Ignacio I. , Futreal Andrew P. , Maru Dipen M. , Solis Soto Luisa M. , Parra Cuentas Edwin R. , Chen Honglei , Villalobos Pamela , Verma Anuj , Mahvash Armeen , Hwu Patrick , Cortazar Patricia , McKenna Edward , Yun Cindy , Dervin Shannon , Schulze Katja , Darbonne Walter C. , Morani Ajaykumar C. , Kopetz Scott , Fournier Keith F. , Woodman Scott E. , Yao James C. , Varadhachary Gauri R. , Halperin Daniel M.
Published: April 2023

Abstract
Malignant peritoneal mesothelioma (MPeM) is a rare but aggressive malignancy with limited treatment options. VEGF inhibition enhances efficacy of immune-checkpoint inhibitors by reworking the immunosuppressive tumor milieu. Efficacy and safety of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) was assessed in 20 patients with advanced and unresectable MPeM with progression or intolerance to prior platinum–pemetrexed chemotherapy. The primary endpoint of confirmed objective response rate per RECISTv1.1 by independent radiology review was 40% [8/20; 95% confidence interval (CI), 19.1–64.0] with median response duration of 12.8 months. Six (75%) responses lasted for >10 months. Progression-free and overall survival at one year were 61% (95% CI, 35–80) and 85% (95% CI, 60–95), respectively. Responses occurred notwithstanding low tumor mutation burden and PD-L1 expression status. Baseline epithelial–mesenchymal transition gene expression correlated with therapeutic resistance/response (r = 0.80; P = 0.0010). AtezoBev showed promising and durable efficacy in patients with advanced MPeM with an acceptable safety profile, and these results address a grave unmet need for this orphan disease.
Significance:
Efficacy of atezolizumab and bevacizumab vis-à-vis response rates and survival in advanced peritoneal mesothelioma previously treated with chemotherapy surpassed outcomes expected with conventional therapies. Biomarker analyses uncovered epithelial–mesenchymal transition phenotype as an important resistance mechanism and showcase the value and feasibility of performing translationally driven clinical trials in rare tumors.

See related commentary by Aldea et al., p. 2674.

This article is highlighted in the In This Issue feature, p. 2659
Data from Repurposing Vandetanib plus Everolimus for the Treatment of ACVR1-Mutant Diffuse Intrinsic Pontine Glioma
Authors: Carvalho Diana M. , Richardson Peter J. , Olaciregui Nagore , Stankunaite Reda , Lavarino Cinzia , Molinari Valeria , Corley Elizabeth A. , Smith Daniel P. , Ruddle Ruth , Donovan Adam , Pal Akos , Raynaud Florence I. , Temelso Sara , Mackay Alan , Overington John P. , Phelan Anne , Sheppard David , Mackinnon Andrew , Zebian Bassel , Al-Sarraj Safa , Merve Ashirwad , Pryce Jeremy , Grill Jacques , Hubank Michael , Cruz Ofelia , Morales La Madrid Andres , Mueller Sabine , Carcaboso Angel M. , Carceller Fernando , Jones Chris
Published: April 2023

Abstract
Somatic mutations in ACVR1 are found in a quarter of children with diffuse intrinsic pontine glioma (DIPG), but there are no ACVR1 inhibitors licensed for the disease. Using an artificial intelligence–based platform to search for approved compounds for ACVR1-mutant DIPG, the combination of vandetanib and everolimus was identified as a possible therapeutic approach. Vandetanib, an inhibitor of VEGFR/RET/EGFR, was found to target ACVR1 (Kd = 150 nmol/L) and reduce DIPG cell viability in vitro but has limited ability to cross the blood–brain barrier. In addition to mTOR, everolimus inhibited ABCG2 (BCRP) and ABCB1 (P-gp) transporters and was synergistic in DIPG cells when combined with vandetanib in vitro. This combination was well tolerated in vivo and significantly extended survival and reduced tumor burden in an orthotopic ACVR1-mutant patient-derived DIPG xenograft model. Four patients with ACVR1-mutant DIPG were treated with vandetanib plus an mTOR inhibitor, informing the dosing and toxicity profile of this combination for future clinical studies.
Significance:
Twenty-five percent of patients with the incurable brainstem tumor DIPG harbor somatic activating mutations in ACVR1, but there are no approved drugs targeting the receptor. Using artificial intelligence, we identify and validate, both experimentally and clinically, the novel combination of vandetanib and everolimus in these children based on both signaling and pharmacokinetic synergies.

This article is highlighted in the In This Issue feature, p. 275
Data from Nongenetic Evolution Drives Lung Adenocarcinoma Spatial Heterogeneity and Progression
Authors: Tavernari Daniele , Battistello Elena , Dheilly Elie , Petruzzella Aaron S. , Mina Marco , Sordet-Dessimoz Jessica , Peters Solange , Krueger Thorsten , Gfeller David , Riggi Nicolo , Oricchio Elisa , Letovanec Igor , Ciriello Giovanni
Published: April 2023

Abstract
Cancer evolution determines molecular and morphologic intratumor heterogeneity and challenges the design of effective treatments. In lung adenocarcinoma, disease progression and prognosis are associated with the appearance of morphologically diverse tumor regions, termed histologic patterns. However, the link between molecular and histologic features remains elusive. Here, we generated multiomics and spatially resolved molecular profiles of histologic patterns from primary lung adenocarcinoma, which we integrated with molecular data from >2,000 patients. The transition from indolent to aggressive patterns was not driven by genetic alterations but by epigenetic and transcriptional reprogramming reshaping cancer cell identity. A signature quantifying this transition was an independent predictor of patient prognosis in multiple human cohorts. Within individual tumors, highly multiplexed protein spatial profiling revealed coexistence of immune desert, inflamed, and excluded regions, which matched histologic pattern composition. Our results provide a detailed molecular map of lung adenocarcinoma intratumor spatial heterogeneity, tracing nongenetic routes of cancer evolution.
Significance:
Lung adenocarcinomas are classified based on histologic pattern prevalence. However, individual tumors exhibit multiple patterns with unknown molecular features. We characterized nongenetic mechanisms underlying intratumor patterns and molecular markers predicting patient prognosis. Intratumor patterns determined diverse immune microenvironments, warranting their study in the context of current immunotherapies.

This article is highlighted in the In This Issue feature, p. 1307
Data from A Phase I Trial of Regional Mesothelin-Targeted CAR T-cell Therapy in Patients with Malignant Pleural Disease, in Combination with the Anti–PD-1 Agent Pembrolizumab
Authors: Adusumilli Prasad S. , Zauderer Marjorie G. , Rivière Isabelle , Solomon Stephen B. , Rusch Valerie W. , O'Cearbhaill Roisin E. , Zhu Amy , Cheema Waseem , Chintala Navin K. , Halton Elizabeth , Pineda John , Perez-Johnston Rocio , Tan Kay See , Daly Bobby , Araujo Filho Jose A. , Ngai Daniel , McGee Erin , Vincent Alain , Diamonte Claudia , Sauter Jennifer L. , Modi Shanu , Sikder Devanjan , Senechal Brigitte , Wang Xiuyan , Travis William D. , Gönen Mithat , Rudin Charles M. , Brentjens Renier J. , Jones David R. , Sadelain Michel
Published: April 2023

Abstract
Malignant pleural diseases, comprising metastatic lung and breast cancers and malignant pleural mesothelioma (MPM), are aggressive solid tumors with poor therapeutic response. We developed and conducted a first-in-human, phase I study of regionally delivered, autologous, mesothelin-targeted chimeric antigen receptor (CAR) T-cell therapy. Intrapleural administration of 0.3M to 60M CAR T cells/kg in 27 patients (25 with MPM) was safe and well tolerated. CAR T cells were detected in peripheral blood for >100 days in 39% of patients. Following our demonstration that PD-1 blockade enhances CAR T-cell function in mice, 18 patients with MPM also received pembrolizumab safely. Among those patients, median overall survival from CAR T-cell infusion was 23.9 months (1-year overall survival, 83%). Stable disease was sustained for ≥6 months in 8 patients; 2 exhibited complete metabolic response on PET scan. Combination immunotherapy with CAR T cells and PD-1 blockade agents should be further evaluated in patients with solid tumors.
Significance:
Regional delivery of mesothelin-targeted CAR T-cell therapy followed by pembrolizumab administration is feasible, safe, and demonstrates evidence of antitumor efficacy in patients with malignant pleural diseases. Our data support the investigation of combination immunotherapy with CAR T cells and PD-1 blockade agents in solid tumors.

See related commentary by Aldea et al., p. 2674.

This article is highlighted in the In This Issue feature, p. 2659
Data from LKB1/STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms
Authors: Marinaccio Christian , Suraneni Praveen , Celik Hamza , Volk Andrew , Wen Qiang Jeremy , Ling Te , Bulic Marinka , Lasho Terra , Koche Richard P. , Famulare Christopher A. , Farnoud Noushin , Stein Brady , Schieber Michael , Gurbuxani Sandeep , Root David E. , Younger Scott T. , Hoffman Ronald , Gangat Naseema , Ntziachristos Panagiotis , Chandel Navdeep S. , Levine Ross L. , Rampal Raajit K. , Challen Grant A. , Tefferi Ayalew , Crispino John D.
Published: April 2023

Abstract
The myeloproliferative neoplasms (MPN) frequently progress to blast phase disease, an aggressive form of acute myeloid leukemia. To identify genes that suppress disease progression, we performed a focused CRISPR/Cas9 screen and discovered that depletion of LKB1/Stk11 led to enhanced in vitro self-renewal of murine MPN cells. Deletion of Stk11 in a mouse MPN model caused rapid lethality with enhanced fibrosis, osteosclerosis, and an accumulation of immature cells in the bone marrow, as well as enhanced engraftment of primary human MPN cells in vivo. LKB1 loss was associated with increased mitochondrial reactive oxygen species and stabilization of HIF1α, and downregulation of LKB1 and increased levels of HIF1α were observed in human blast phase MPN specimens. Of note, we observed strong concordance of pathways that were enriched in murine MPN cells with LKB1 loss with those enriched in blast phase MPN patient specimens, supporting the conclusion that STK11 is a tumor suppressor in the MPNs.
Significance:
Progression of the myeloproliferative neoplasms to acute myeloid leukemia occurs in a substantial number of cases, but the genetic basis has been unclear. We discovered that loss of LKB1/STK11 leads to stabilization of HIF1a and promotes disease progression. This observation provides a potential therapeutic avenue for targeting progression.

This article is highlighted in the In This Issue feature, p. 1307
Data from Prolonged SARS-CoV-2 Infection in Patients with Lymphoid Malignancies
Authors: Lee Christina Y. , Shah Monika K. , Hoyos David , Solovyov Alexander , Douglas Melanie , Taur Ying , Maslak Peter , Babady N. Esther , Greenbaum Benjamin , Kamboj Mini , Vardhana Santosha A.
Published: April 2023

Abstract
Coronavirus disease 2019 (COVID-19) infection results in both acute mortality and persistent and/or recurrent disease in patients with hematologic malignancies, but the drivers of persistent infection in this population are unknown. We found that B-cell lymphomas were at particularly high risk for persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity. Further analysis of these patients identified discrete risk factors for initial disease severity compared with disease chronicity. Active therapy and diminished T-cell counts were drivers of acute mortality in COVID-19–infected patients with lymphoma. Conversely, B cell–depleting therapy was the primary driver of rehospitalization for COVID-19. In patients with persistent SARS-CoV-2 positivity, we observed high levels of viral entropy consistent with intrahost viral evolution, particularly in patients with impaired CD8+ T-cell immunity. These results suggest that persistent COVID-19 infection is likely to remain a risk in patients with impaired adaptive immunity and that additional therapeutic strategies are needed to enable viral clearance in this high-risk population.
Significance:
We describe the largest cohort of persistent symptomatic COVID-19 infection in patients with lymphoid malignancies and identify B-cell depletion as the key immunologic driver of persistent infection. Furthermore, we demonstrate ongoing intrahost viral evolution in patients with persistent COVID-19 infection, particularly in patients with impaired CD8+ T-cell immunity.

This article is highlighted in the In This Issue feature, p. 1