bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression
Authors: Rusan Maria , Li Kapsok , Li Yvonne , Christensen Camilla L. , Abraham Brian J. , Kwiatkowski Nicholas , Buczkowski Kevin A. , Bockorny Bruno , Chen Ting , Li Shuai , Rhee Kevin , Zhang Haikuo , Chen Wankun , Terai Hideki , Tavares Tiffany , Leggett Alan L. , Li Tianxia , Wang Yichen , Zhang Tinghu , Kim Tae-Jung , Hong Sook-Hee , Poudel-Neupane Neermala , Silkes Michael , Mudianto Tenny , Tan Li , Shimamura Takeshi , Meyerson Matthew , Bass Adam J. , Watanabe Hideo , Gray Nathanael S. , Young Richard A. , Wong Kwok-Kin , Hammerman Peter S.
Published: March 2024

Abstract
Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.

Significance: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies. Cancer Discov; 8(1); 59–73. ©2017 AACR.

See related commentary by Carugo and Draetta, p. 17.

This article is highlighted in the In This Issue feature, p. 1
Data from Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma
Authors: Pectasides Eirini , Stachler Matthew D. , Derks Sarah , Liu Yang , Maron Steven , Islam Mirazul , Alpert Lindsay , Kwak Heewon , Kindler Hedy , Polite Blase , Sharma Manish R. , Allen Kenisha , O'Day Emily , Lomnicki Samantha , Maranto Melissa , Kanteti Rajani , Fitzpatrick Carrie , Weber Christopher , Setia Namrata , Xiao Shu-Yuan , Hart John , Nagy Rebecca J. , Kim Kyoung-Mee , Choi Min-Gew , Min Byung-Hoon , Nason Katie S. , O'Keefe Lea , Watanabe Masayuki , Baba Hideo , Lanman Rick , Agoston Agoston T. , Oh David J. , Dunford Andrew , Thorner Aaron R. , Ducar Matthew D. , Wollison Bruce M. , Coleman Haley A. , Ji Yuan , Posner Mitchell C. , Roggin Kevin , Turaga Kiran , Chang Paul , Hogarth Kyle , Siddiqui Uzma , Gelrud Andres , Ha Gavin , Freeman Samuel S. , Rhoades Justin , Reed Sarah , Gydush Greg , Rotem Denisse , Davison Jon , Imamura Yu , Adalsteinsson Viktor , Lee Jeeyun , Bass Adam J. , Catenacci Daniel V.
Published: March 2024

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

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

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

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

This article is highlighted in the In This Issue feature, p. 1
Data from Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors
Authors: Tsurutani Junji , Iwata Hiroji , Krop Ian , Jänne Pasi A. , Doi Toshihiko , Takahashi Shunji , Park Haeseong , Redfern Charles , Tamura Kenji , Wise-Draper Trisha M. , Saito Kaku , Sugihara Masahiro , Singh Jasmeet , Jikoh Takahiro , Gallant Gilles , Li Bob T.
Published: March 2024

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

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

This article is highlighted in the In This Issue feature, p. 627
Data from Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer
Authors: Parker Seth J. , Amendola Caroline R. , Hollinshead Kate E.R. , Yu Qijia , Yamamoto Keisuke , Encarnación-Rosado Joel , Rose Rebecca E. , LaRue Madeleine M. , Sohn Albert S.W. , Biancur Doug E. , Paulo Joao A. , Gygi Steven P. , Jones Drew R. , Wang Huamin , Philips Mark R. , Bar-Sagi Dafna , Mancias Joseph D. , Kimmelman Alec C.
Published: March 2024

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

This article is highlighted in the In This Issue feature, p. 890
Data from Relapse-Fated Latent Diagnosis Subclones in Acute B Lineage Leukemia Are Drug Tolerant and Possess Distinct Metabolic Programs
Authors: Dobson Stephanie M. , García-Prat Laura , Vanner Robert J. , Wintersinger Jeffrey , Waanders Esmé , Gu Zhaohui , McLeod Jessica , Gan Olga I. , Grandal Ildiko , Payne-Turner Debbie , Edmonson Michael N. , Ma Xiaotu , Fan Yiping , Voisin Veronique , Chan-Seng-Yue Michelle , Xie Stephanie Z. , Hosseini Mohsen , Abelson Sagi , Gupta Pankaj , Rusch Michael , Shao Ying , Olsen Scott R. , Neale Geoffrey , Chan Steven M. , Bader Gary , Easton John , Guidos Cynthia J. , Danska Jayne S. , Zhang Jinghui , Minden Mark D. , Morris Quaid , Mullighan Charles G. , Dick John E.
Published: March 2024

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

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

See related article by E. Waanders et al.
Data from Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade
Authors: Zhang Qu , Luo Jia , Wu Song , Si Han , Gao Chen , Xu Wenjing , Abdullah Shaad E. , Higgs Brandon W. , Dennis Phillip A. , van der Heijden Michiel S. , Segal Neil H. , Chaft Jamie E. , Hembrough Todd , Barrett J. Carl , Hellmann Matthew D.
Published: March 2024

Abstract
The utility of circulating tumor DNA (ctDNA) as a biomarker in patients with advanced cancers receiving immunotherapy is uncertain. We therefore analyzed pretreatment (n = 978) and on-treatment (n = 171) ctDNA samples across 16 advanced-stage tumor types from three phase I/II trials of durvalumab (± the anti-CTLA4 therapy tremelimumab). Higher pretreatment variant allele frequencies (VAF) were associated with poorer overall survival (OS) and other known prognostic factors, but not objective response, suggesting a prognostic role for patient outcomes. On-treatment reductions in VAF and lower on-treatment VAF were independently associated with longer progression-free survival and OS and increased objective response rate, but not prognostic variables, suggesting that on-treatment ctDNA dynamics are predictive of benefit from immune checkpoint blockade. Accordingly, we propose a concept of “molecular response” using ctDNA, incorporating both pretreatment and on-treatment VAF, that predicted long-term survival similarly to initial radiologic response while also permitting early differentiation of responders among patients with initially radiologically stable disease.
Significance:
In a pan-cancer analysis of immune checkpoint blockade, pretreatment ctDNA levels appeared prognostic and on-treatment dynamics predictive. A “molecular response” metric identified long-term responders and adjudicated benefit among patients with initially radiologically stable disease. Changes in ctDNA may be more dynamic than radiographic changes and could complement existing trial endpoints.

This article is highlighted in the In This Issue feature, p. 1775
Data from Identification of BBOX1 as a Therapeutic Target in Triple-Negative Breast Cancer
Authors: Liao Chengheng , Zhang Yang , Fan Cheng , Herring Laura E. , Liu Juan , Locasale Jason W. , Takada Mamoru , Zhou Jin , Zurlo Giada , Hu Lianxin , Simon Jeremy M. , Ptacek Travis S. , Andrianov Victor G. , Loza Einars , Peng Yan , Yang Huanghe , Perou Charles M. , Zhang Qing
Published: March 2024

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

This article is highlighted in the In This Issue feature, p. 1611
Data from The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer
Authors: Wander Seth A. , Cohen Ofir , Gong Xueqian , Johnson Gabriela N. , Buendia-Buendia Jorge E. , Lloyd Maxwell R. , Kim Dewey , Luo Flora , Mao Pingping , Helvie Karla , Kowalski Kailey J. , Nayar Utthara , Waks Adrienne G. , Parsons Stephen H. , Martinez Ricardo , Litchfield Lacey M. , Ye Xiang S. , Yu Chunping , Jansen Valerie M. , Stille John R. , Smith Patricia S. , Oakley Gerard J. , Chu Quincy S. , Batist Gerald , Hughes Melissa E. , Kremer Jill D. , Garraway Levi A. , Winer Eric P. , Tolaney Sara M. , Lin Nancy U. , Buchanan Sean G. , Wagle Nikhil
Published: March 2024

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

This article is highlighted in the In This Issue feature, p. 1079
Data from Gain-of-Function Genetic Alterations of G9a Drive Oncogenesis
Authors: Kato Shinichiro , Weng Qing Yu , Insco Megan L. , Chen Kevin Y. , Muralidhar Sathya , Pozniak Joanna , Diaz Joey Mark S. , Drier Yotam , Nguyen Nhu , Lo Jennifer A. , van Rooijen Ellen , Kemeny Lajos V. , Zhan Yao , Feng Yang , Silkworth Whitney , Powell C. Thomas , Liau Brian B. , Xiong Yan , Jin Jian , Newton-Bishop Julia , Zon Leonard I. , Bernstein Bradley E. , Fisher David E.
Published: March 2024

Abstract
Epigenetic regulators, when genomically altered, may become driver oncogenes that mediate otherwise unexplained pro-oncogenic changes lacking a clear genetic stimulus, such as activation of the WNT/β-catenin pathway in melanoma. This study identifies previously unrecognized recurrent activating mutations in the G9a histone methyltransferase gene, as well as G9a genomic copy gains in approximately 26% of human melanomas, which collectively drive tumor growth and an immunologically sterile microenvironment beyond melanoma. Furthermore, the WNT pathway is identified as a key tumorigenic target of G9a gain-of-function, via suppression of the WNT antagonist DKK1. Importantly, genetic or pharmacologic suppression of mutated or amplified G9a using multiple in vitro and in vivo models demonstrates that G9a is a druggable target for therapeutic intervention in melanoma and other cancers harboring G9a genomic aberrations.
Significance:
Oncogenic G9a abnormalities drive tumorigenesis and the “cold” immune microenvironment by activating WNT signaling through DKK1 repression. These results reveal a key druggable mechanism for tumor development and identify strategies to restore “hot” tumor immune microenvironments.

This article is highlighted in the In This Issue feature, p. 890
Data from The Meningioma Enhancer Landscape Delineates Novel Subgroups and Drives Druggable Dependencies
Authors: Prager Briana C. , Vasudevan Harish N. , Dixit Deobrat , Bernatchez Jean A. , Wu Qiulian , Wallace Lisa C. , Bhargava Shruti , Lee Derrick , King Bradley H. , Morton Andrew R. , Gimple Ryan C. , Pekmezci Melike , Zhu Zhe , Siqueira-Neto Jair L. , Wang Xiuxing , Xie Qi , Chen Clark , Barnett Gene H. , Vogelbaum Michael A. , Mack Stephen C. , Chavez Lukas , Perry Arie , Raleigh David R. , Rich Jeremy N.
Published: March 2024

Abstract
Meningiomas are the most common primary intracranial tumor with current classification offering limited therapeutic guidance. Here, we interrogated meningioma enhancer landscapes from 33 tumors to stratify patients based upon prognosis and identify novel meningioma-specific dependencies. Enhancers robustly stratified meningiomas into three biologically distinct groups (adipogenesis/cholesterol, mesodermal, and neural crest) distinguished by distinct hormonal lineage transcriptional regulators. Meningioma landscapes clustered with intrinsic brain tumors and hormonally responsive systemic cancers with meningioma subgroups, reflecting progesterone or androgen hormonal signaling. Enhancer classification identified a subset of tumors with poor prognosis, irrespective of histologic grading. Superenhancer signatures predicted drug dependencies with superior in vitro efficacy to treatment based upon the NF2 genomic profile. Inhibition of DUSP1, a novel and druggable meningioma target, impaired tumor growth in vivo. Collectively, epigenetic landscapes empower meningioma classification and identification of novel therapies.
Significance:
Enhancer landscapes inform prognostic classification of aggressive meningiomas, identifying tumors at high risk of recurrence, and reveal previously unknown therapeutic targets. Druggable dependencies discovered through epigenetic profiling potentially guide treatment of intractable meningiomas.

This article is highlighted in the In This Issue feature, p. 1611
Data from Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction
Authors: Singh Nathan , Lee Yong Gu , Shestova Olga , Ravikumar Pranali , Hayer Katharina E. , Hong Seok Jae , Lu Xueqing Maggie , Pajarillo Raymone , Agarwal Sangya , Kuramitsu Shunichiro , Orlando Elena J. , Mueller Karen Thudium , Good Charly R. , Berger Shelley L. , Shalem Ophir , Weitzman Matthew D. , Frey Noelle V. , Maude Shannon L. , Grupp Stephan A. , June Carl H. , Gill Saar , Ruella Marco
Published: March 2024

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

See related commentary by Green and Neelapu, p. 492.
Data from Cell of Origin Influences Pancreatic Cancer Subtype
Authors: Flowers Brittany M. , Xu Hang , Mulligan Abigail S. , Hanson Kathryn J. , Seoane Jose A. , Vogel Hannes , Curtis Christina , Wood Laura D. , Attardi Laura D.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of approximately 9%. An improved understanding of PDAC initiation and progression is paramount for discovering strategies to better detect and combat this disease. Although transcriptomic analyses have uncovered distinct molecular subtypes of human PDAC, the factors that influence subtype development remain unclear. Here, we interrogate the impact of cell of origin and different Trp53 alleles on tumor evolution, using a panel of tractable genetically engineered mouse models. Oncogenic KRAS expression, coupled with Trp53 deletion or point mutation, drives PDAC from both acinar and ductal cells. Gene-expression analysis reveals further that ductal cell–derived and acinar cell–derived tumor signatures are enriched in basal-like and classical subtypes of human PDAC, respectively. These findings highlight cell of origin as one factor that influences PDAC molecular subtypes and provide insight into the fundamental impact that the very earliest events in carcinogenesis can have on cancer evolution.
Significance:
Although human PDAC has been classified into different molecular subtypes, the etiology of these distinct subtypes remains unclear. Using mouse genetics, we reveal that cell of origin is an important determinant of PDAC molecular subtype. Deciphering the biology underlying pancreatic cancer subtypes may reveal meaningful distinctions that could improve clinical intervention.

This article is highlighted in the In This Issue feature, p. 521
Data from Repression of the Type I Interferon Pathway Underlies MYC- and KRAS-Dependent Evasion of NK and B Cells in Pancreatic Ductal Adenocarcinoma
Authors: Muthalagu Nathiya , Monteverde Tiziana , Raffo-Iraolagoitia Ximena , Wiesheu Robert , Whyte Declan , Hedley Ann , Laing Sarah , Kruspig Björn , Upstill-Goddard Rosanna , Shaw Robin , Neidler Sarah , Rink Curtis , Karim Saadia A. , Gyuraszova Katarina , Nixon Colin , Clark William , Biankin Andrew V. , Carlin Leo M. , Coffelt Seth B. , Sansom Owen J. , Morton Jennifer P. , Murphy Daniel J.
Published: March 2024

Abstract
MYC is implicated in the development and progression of pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumor development has been difficult to define. We used modestly elevated expression of human MYC, driven from the Rosa26 locus, to investigate the pancreatic phenotypes arising in mice from an approximation of MYC trisomy. We show that this level of MYC alone suffices to drive pancreatic neuroendocrine tumors, and to accelerate progression of KRAS-initiated precursor lesions to metastatic pancreatic ductal adenocarcinoma (PDAC). Our phenotype exposed suppression of the type I interferon (IFN) pathway by the combined actions of MYC and KRAS, and we present evidence of repressive MYC–MIZ1 complexes binding directly to the promoters of the genes encodiing the type I IFN regulators IRF5, IRF7, STAT1, and STAT2. Derepression of IFN regulator genes allows pancreatic tumor infiltration by B and natural killer (NK) cells, resulting in increased survival.
Significance:
We define herein a novel mechanism of evasion of NK cell–mediated immunity through the combined actions of endogenously expressed mutant KRAS and modestly deregulated expression of MYC, via suppression of the type I IFN pathway. Restoration of IFN signaling may improve outcomes for patients with PDAC.

This article is highlighted in the In This Issue feature, p. 747
Data from TBK1 Is a Synthetic Lethal Target in Cancer with VHL Loss
Authors: Hu Lianxin , Xie Haibiao , Liu Xijuan , Potjewyd Frances , James Lindsey I. , Wilkerson Emily M. , Herring Laura E. , Xie Ling , Chen Xian , Cabrera Johnny Castillo , Hong Kai , Liao Chengheng , Tan Xianming , Baldwin Albert S. , Gong Kan , Zhang Qing
Published: March 2024

Abstract
TANK binding kinase 1 (TBK1) is an important kinase involved in the innate immune response. Here we discover that TBK1 is hyperactivated by von Hippel-Lindau (VHL) loss or hypoxia in cancer cells. Tumors from patients with kidney cancer with VHL loss display elevated TBK1 phosphorylation. Loss of TBK1 via genetic ablation, pharmacologic inhibition, or a new cereblon-based proteolysis targeting chimera specifically inhibits VHL-deficient kidney cancer cell growth, while leaving VHL wild-type cells intact. TBK1 depletion also significantly blunts kidney tumorigenesis in an orthotopic xenograft model in vivo. Mechanistically, TBK1 hydroxylation on Proline 48 triggers VHL as well as the phosphatase PPM1B binding that leads to decreased TBK1 phosphorylation. We identify that TBK1 phosphorylates p62/SQSTM1 on Ser366, which is essential for p62 stability and kidney cancer cell proliferation. Our results establish that TBK1, distinct from its role in innate immune signaling, is a synthetic lethal target in cancer with VHL loss.
Significance:
The mechanisms that lead to TBK1 activation in cancer and whether this activation is connected to its role in innate immunity remain unclear. Here, we discover that TBK1, distinct from its role in innate immunity, is activated by VHL loss or hypoxia in cancer.

See related commentary by Bakouny and Barbie, p. 348.

This article is highlighted in the In This Issue feature, p. 327
Data from Resistance Mechanisms to SYK Inhibition in Acute Myeloid Leukemia
Authors: Cremer Anjali , Ellegast Jana M. , Alexe Gabriela , Frank Elizabeth S. , Ross Linda , Chu S. Haihua , Pikman Yana , Robichaud Amanda , Goodale Amy , Häupl Björn , Mohr Sebastian , Rao Arati V. , Walker Alison R. , Blachly James S. , Piccioni Federica , Armstrong Scott A. , Byrd John C. , Oellerich Thomas , Stegmaier Kimberly
Published: March 2024

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

This article is highlighted in the In This Issue feature, p. 161
Data from The INPP4B Tumor Suppressor Modulates EGFR Trafficking and Promotes Triple-Negative Breast Cancer
Authors: Liu Hui , Paddock Marcia N. , Wang Haibin , Murphy Charles J. , Geck Renee C. , Navarro Adrija J. , Wulf Gerburg M. , Elemento Olivier , Haucke Volker , Cantley Lewis C. , Toker Alex
Published: March 2024

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

This article is highlighted in the In This Issue feature, p. 1079
Data from Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non–BRCA1/2-Mutant Cancers
Authors: Yap Timothy A. , Kristeleit Rebecca , Michalarea Vasiliki , Pettitt Stephen J. , Lim Joline S.J. , Carreira Suzanne , Roda Desamparados , Miller Rowan , Riisnaes Ruth , Miranda Susana , Figueiredo Ines , Rodrigues Daniel Nava , Ward Sarah , Matthews Ruth , Parmar Mona , Turner Alison , Tunariu Nina , Chopra Neha , Gevensleben Heidrun , Turner Nicholas C. , Ruddle Ruth , Raynaud Florence I. , Decordova Shaun , Swales Karen E. , Finneran Laura , Hall Emma , Rugman Paul , Lindemann Justin P.O. , Foxley Andrew , Lord Christopher J. , Banerji Udai , Plummer Ruth , Basu Bristi , Lopez Juanita S. , Drew Yvette , de Bono Johann S.
Published: March 2024

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

This article is highlighted in the In This Issue feature, p. 1426
Data from Polyunsaturated Fatty Acids from Astrocytes Activate PPARγ Signaling in Cancer Cells to Promote Brain Metastasis
Authors: Zou Yongkang , Watters Andrea , Cheng Nan , Perry Caroline E. , Xu Ke , Alicea Gretchen M. , Parris Joshua L.D. , Baraban Ezra , Ray Pulak , Nayak Anupma , Xu Xiaowei , Herlyn Meenhard , Murphy Maureen E. , Weeraratna Ashani T. , Schug Zachary T. , Chen Qing
Published: March 2024

Abstract
Brain metastasis, the most lethal form of melanoma and carcinoma, is the consequence of favorable interactions between the invading cancer cells and the brain cells. Peroxisome proliferator–activated receptor γ (PPARγ) has ambiguous functions in cancer development, and its relevance in advanced brain metastasis remains unclear. Here, we demonstrate that astrocytes, the unique brain glial cells, activate PPARγ in brain metastatic cancer cells. PPARγ activation enhances cell proliferation and metastatic outgrowth in the brain. Mechanistically, astrocytes have a high content of polyunsaturated fatty acids that act as “donors” of PPARγ activators to the invading cancer cells. In clinical samples, PPARγ signaling is significantly higher in brain metastatic lesions. Notably, systemic administration of PPARγ antagonists significantly reduces brain metastatic burden in vivo. Our study clarifies a prometastatic role for PPARγ signaling in cancer metastasis in the lipid-rich brain microenvironment and argues for the use of PPARγ blockade to treat brain metastasis.
Significance:
Brain-tropic cancer cells take advantage of the lipid-rich brain microenvironment to facilitate their proliferation by activating PPARγ signaling. This protumor effect of PPARγ in advanced brain metastases is in contrast to its antitumor function in carcinogenesis and early metastatic steps, indicating that PPARγ has diverse functions at different stages of cancer development.

This article is highlighted in the In This Issue feature, p. 1631
Data from Genetically Defined, Syngeneic Organoid Platform for Developing Combination Therapies for Ovarian Cancer
Authors: Zhang Shuang , Iyer Sonia , Ran Hao , Dolgalev Igor , Gu Shengqing , Wei Wei , Foster Connor J.R. , Loomis Cynthia A. , Olvera Narciso , Dao Fanny , Levine Douglas A. , Weinberg Robert A. , Neel Benjamin G.
Published: March 2024

Abstract
The paucity of genetically informed, immunocompetent tumor models impedes evaluation of conventional, targeted, and immune therapies. By engineering mouse fallopian tube epithelial organoids using lentiviral gene transduction and/or CRISPR/Cas9 mutagenesis, we generated multiple high-grade serous tubo-ovarian cancer (HGSC) models exhibiting mutational combinations seen in patients with HGSC. Detailed analysis of homologous recombination (HR)–proficient (Trp53−/−;Ccne1OE;Akt2OE;KrasOE), HR-deficient (Trp53−/−;Brca1−/−;MycOE), and unclassified (Trp53−/−;Pten−/−;Nf1−/−) organoids revealed differences in in vitro properties (proliferation, differentiation, and “secretome”), copy-number aberrations, and tumorigenicity. Tumorigenic organoids had variable sensitivity to HGSC chemotherapeutics, and evoked distinct immune microenvironments that could be modulated by neutralizing organoid-produced chemokines/cytokines. These findings enabled development of a chemotherapy/immunotherapy regimen that yielded durable, T cell–dependent responses in Trp53−/−;Ccne1OE;Akt2OE;Kras HGSC; in contrast, Trp53−/−;Pten−/−;Nf1−/− tumors failed to respond. Mouse and human HGSC models showed genotype-dependent similarities in chemosensitivity, secretome, and immune microenvironment. Genotype-informed, syngeneic organoid models could provide a platform for the rapid evaluation of tumor biology and therapeutics.
Significance:
The lack of genetically informed, diverse, immunocompetent models poses a major barrier to therapeutic development for many malignancies. Using engineered fallopian tube organoids to study the cell-autonomous and cell-nonautonomous effects of specific combinations of mutations found in HGSC, we suggest an effective combination treatment for the currently intractable CCNE1-amplified subgroup.

This article is highlighted in the In This Issue feature, p. 211
Data from Intraductal Transplantation Models of Human Pancreatic Ductal Adenocarcinoma Reveal Progressive Transition of Molecular Subtypes
Authors: Miyabayashi Koji , Baker Lindsey A. , Deschênes Astrid , Traub Benno , Caligiuri Giuseppina , Plenker Dennis , Alagesan Brinda , Belleau Pascal , Li Siran , Kendall Jude , Jang Gun Ho , Kawaguchi Risa Karakida , Somerville Tim D.D. , Tiriac Hervé , Hwang Chang-Il , Burkhart Richard A. , Roberts Nicholas J. , Wood Laura D. , Hruban Ralph H. , Gillis Jesse , Krasnitz Alexander , Vakoc Christopher R. , Wigler Michael , Notta Faiyaz , Gallinger Steven , Park Youngkyu , Tuveson David A.
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated; however, the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively. Parameters that influence PDAC subtype specification in this intraductal model include cell plasticity and hyperactivation of the RAS pathway. Finally, through intratumoral dissection and the direct manipulation of RAS gene dosage, we identify a suite of RAS-regulated secreted and membrane-bound proteins that may represent potential candidates for therapeutic intervention in patients with PDAC.
Significance:
Accurate modeling of the molecular subtypes of pancreatic cancer is crucial to facilitate the generation of effective therapies. We report the development of an intraductal organoid transplantation model of pancreatic cancer that models the progressive switching of subtypes, and identify stochastic and RAS-driven mechanisms that determine subtype specification.

See related commentary by Pickering and Morton, p. 1448.

This article is highlighted in the In This Issue feature, p. 1426
Data from Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity
Authors: Hong Aayoung , Piva Marco , Liu Sixue , Hugo Willy , Lomeli Shirley H. , Zoete Vincent , Randolph Christopher E. , Yang Zhentao , Wang Yan , Lee Jordan J. , Lo Skylar J. , Sun Lu , Vega-Crespo Agustin , Garcia Alejandro J. , Shackelford David B. , Dubinett Steven M. , Scumpia Philip O. , Byrum Stephanie D. , Tackett Alan J. , Donahue Timothy R. , Michielin Olivier , Holmen Sheri L. , Ribas Antoni , Moriceau Gatien , Lo Roger S.
Published: March 2024

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

This article is highlighted in the In This Issue feature, p. 521
Data from Lineage Reversion Drives WNT Independence in Intestinal Cancer
Authors: Han Teng , Goswami Sukanya , Hu Yang , Tang Fanying , Zafra Maria Paz , Murphy Charles , Cao Zhen , Poirier John T. , Khurana Ekta , Elemento Olivier , Hechtman Jaclyn F. , Ganesh Karuna , Yaeger Rona , Dow Lukas E.
Published: March 2024

Abstract
The WNT pathway is a fundamental regulator of intestinal homeostasis, and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer. To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that although WNT suppression blocks tumor growth in most organoid and in vivo colorectal cancer models, the accumulation of colorectal cancer–associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of TP53 and SMAD4, transient TGFβ exposure drives YAP/TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work identifies genetic and microenvironmental factors that drive WNT inhibitor resistance, defines a new mechanism for WNT-independent colorectal cancer growth, and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.
Significance:
Colorectal and intestinal cancers are driven by mutations in the WNT pathway, and drugs aimed at suppressing WNT signaling are in active clinical development. Our study identifies a mechanism of acquired resistance to WNT inhibition and highlights a potential strategy to target those drug-resistant cells.

This article is highlighted in the In This Issue feature, p. 1426
Data from Clinical BRCA1/2 Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance
Authors: Pettitt Stephen J. , Frankum Jessica R. , Punta Marco , Lise Stefano , Alexander John , Chen Yi , Yap Timothy A. , Haider Syed , Tutt Andrew N.J. , Lord Christopher J.
Published: March 2024

Abstract
Reversion mutations in BRCA1 or BRCA2 are associated with resistance to PARP inhibitors and platinum. To better understand the nature of these mutations, we collated, codified, and analyzed more than 300 reversions. This identified reversion “hotspots” and “deserts” in regions encoding the N and C terminus, respectively, of BRCA2, suggesting that pathogenic mutations in these regions may be at higher or lower risk of reversion. Missense and splice-site pathogenic mutations in BRCA1/2 also appeared less likely to revert than truncating mutations. Most reversions were <100 bp deletions. Although many deletions exhibited microhomology, this was not universal, suggesting that multiple DNA-repair processes cause reversion. Finally, we found that many reversions were predicted to encode immunogenic neopeptides, suggesting a route to the treatment of reverted disease. As well as providing a freely available database for the collation of future reversion cases, these observations have implications for how drug resistance might be managed in BRCA-mutant cancers.
Significance:
Reversion mutations in BRCA genes are a major cause of clinical platinum and PARP inhibitor resistance. This analysis of all reported clinical reversions suggests that the position of BRCA2 mutations affects the risk of reversion. Many reversions are also predicted to encode tumor neoantigens, providing a potential route to targeting resistance.

This article is highlighted in the In This Issue feature, p. 1426