Cancer research最新文献

{"title":"THE STING AGONIST VB-85247 INDUCES DURABLE ANTITUMOR IMMUNE RESPONSES BY INTRAVESICAL ADMINISTRATION IN A NON-MUSCLE INVASIVE BLADDER CANCER","authors":"Miglena G. Prabagar, Michael McQueney, Venu Bommireddy, Rachael Siegel, Gary L. Schieven, Ku Lu, Ruziboy Husanov, Reema Deepak, David Diller, Chia-Yu Huang, Eli Mordechai, Rukiye-Nazan Eraslan","doi":"10.1158/0008-5472.can-24-1022","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1022","url":null,"abstract":"Bacillus Calmette-Guerin (BCG) is the current standard of care for non-muscle invasive bladder cancer (NMIBC), but recurrence is common. Additional therapeutic options are a major unmet medical need for treating unresponsive patients. Stimulator of Interferon Genes (STING) plays a central role in mounting innate and adaptive immune responses to tumor cells, and activation of STING is a promising immunotherapeutic approach. Here, we developed the STING agonist VB-85247 for treating NMIBC by intravesical delivery as a strategy to provide a sustained period of exposure to bladder cancer cells while avoiding potential issues associated with intratumoral injection of STING agonist, which to date have shown only limited clinical efficacy. VB-85247 induced complete response in an orthotopic NMIBC model in contrast to treatment with BCG, which was not efficasious in the model. The efficacious dose was well tolerated and induced an immune response with immunologic memory which protected from re-challenge without further treatment. Activation of the STING pathway via VB-85247 induced upregulation of inflammatory cytokines IFN-/β, TNF-, IL-6 and CXCL10, along with maturation and activation of dendritic cells. In addition, VB-85247 provided a therapeutic benefit in combination with immune checkpoint blockade using anti-PD1 antibody treatment. Together, these preclinical data support the potential utility of VB-85247 for treating BCG-unresponsive NMIBC patients and for enhancing the clinical benefit of potential of anti-PD1 in bladder cancer. Based on these data, VB-85247 is being advanced into clinical development.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"86 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatiotemporal Profiling Defines Persistence and Resistance Dynamics During Targeted Treatment of Melanoma","authors":"Jill C. Rubinstein, Sergii Domanskyi, Todd B. Sheridan, Brian Sanderson, SungHee Park, Jessica Kaster, Haiyin Li, Olga Anczukow, Meenhard Herlyn, Jeffrey H. Chuang","doi":"10.1158/0008-5472.can-24-0690","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0690","url":null,"abstract":"Resistance of BRAF-mutant melanomas to targeted therapy arises from the ability of cells to enter a persister state, evade treatment with relative dormancy, and repopulate the tumor when reactivated. A better understanding of the temporal dynamics and specific pathways leading into and out of the persister state is needed to identify strategies to prevent treatment failure. Using spatial transcriptomics in patient-derived xenograft models, we captured clonal lineage evolution during treatment. The persister state showed increased oxidative phosphorylation, decreased proliferation, and increased invasive capacity, with central-to-peripheral gradients. Phylogenetic tracing identified intrinsic and acquired resistance mechanisms (e.g., dual specific phosphatases, reticulon-4, and CDK2) and suggested specific temporal windows of potential therapeutic susceptibility. Deep learning-enabled analysis of histopathological slides revealed morphological features correlating with specific cell states, demonstrating that juxtaposition of transcriptomics and histological data enabled identification of phenotypically distinct populations from using imaging data alone. In summary, this study defined state change and lineage selection during melanoma treatment with spatiotemporal resolution, elucidating how choice and timing of therapeutic agents will impact the ability to eradicate resistant clones.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"48 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity","authors":"Luiza Martins. Nascentes Melo, Marie Sabatier, Vijayashree Ramesh, Krystina J. Szylo, Cameron S. Fraser, Alexandra Pon, Evann C. Mitchell, Kelly A. Servage, Gabriele Allies, Isa V. Westedt, Feyza Cansiz, Jonathan Krystkiewicz, Andrea Kutritz, Dirk Schadendorf, Sean J. Morrison, Jessalyn M. Ubellacker, Anju Sreelatha, Alpaslan Tasdogan","doi":"10.1158/0008-5472.can-23-2194","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-2194","url":null,"abstract":"Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a post-translational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to impact metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homologue of SELENOO. Here, we revealed that SELENOO promotes cancer metastasis and identified substrates of SELENOO in mammalian mitochondria. In patients with melanoma, high SELENOO expression was correlated with metastasis and poor overall survival. In a murine model of spontaneous melanoma metastasis, SELENOO deficiency significantly reduced metastasis to distant visceral organs, which could be rescued by treatment with the antioxidant N-acetylcysteine. Mechanistically, SELENOO AMPylated multiple mitochondrial substrates, including succinate dehydrogenase subunit A, one of the four key subunits of mitochondrial complex II. Consistently, SELENOO-deficient cells featured increased mitochondrial complex II activity. Together, these findings demonstrate that SELENOO deficiency limits melanoma metastasis by modulating mitochondrial function and oxidative stress.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"100 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DOT1L mediates stem cell maintenance and represents a therapeutic vulnerability in cancer","authors":"Hetakshi P. Kurani, Joyce M. Slingerland","doi":"10.1158/0008-5472.can-24-3304","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3304","url":null,"abstract":"Tumor-initiating cancer stem cells (CSC) pose a challenge in human malignancies since they are largely treatment resistant and can seed local recurrence and metastasis. Epigenetic mechanisms governing cell fate decisions in embryonic and adult stem cells are deregulated in CSCs. This review focuses on the methyltransferase DOT1L, which methylates H3K79 and is a key epigenetic regulator governing embryonic organogenesis and adult tissue stem cell maintenance. DOT1L is overexpressed in many human malignancies, and dysregulated H3K79 methylation is pathogenic in acute myeloid leukemia and several solid tumors. DOT1L regulates core stem cell genes governing CSC self-renewal, tumorigenesis, and multidrug resistance. Recent work has situated DOT1L as an attractive stem cell target in cancer. These reports showed that DOT1L is overexpressed and its protein activated specifically in malignant stem cells compared to bulk tumor cells, making them vulnerable to DOT1L inhibition in vitro and in vivo. While early DOT1L inhibitor clinical trials were limited by inadequate drug bioavailability, accumulating preclinical data indicate that DOT1L critically regulates CSC self-renewal and might be more effective when given with other anticancer therapies. The appropriate combinations of DOT1L inhibitors with other agents and the sequence and timing of drug delivery for maximum efficacy warrant further investigation.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"55 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Pan-RAS Inhibitor with a Unique Mechanism of Action Blocks Tumor Growth and Induces Antitumor Immunity in Gastrointestinal Cancer","authors":"Jeremy B. Foote, Tyler E. Mattox, Adam B. Keeton, Xi Chen, Forrest T. Smith, Kristy Berry, Thomas W. Holmes, Junwei Wang, Chung-hui Huang, Antonio Ward, AMIT K. Mitra, Veronica Ramirez-Alcantara, Cherlene Hardy, Karianne G. Fleten, Kjersti Flatmark, Karina J. Yoon, Sujith Sarvesh, Ganji P. Nagaraju, Dhana Sekhar Reddy Bandi, Yulia Y. Maxuitenko, Jacaob Valiyaveettil, Julienne L. Carstens, Donald J. Buchsbaum, Jennifer Yang, Gang Zhou, Elmar Nurmemmedov, Ivan Babic, Vadim Gaponeko, Hazem Abdelkarim, Michael R. Boyd, Greg Gorman, Upender Manne, Sejong Bae, Bassel F. El-Rayes, Gary A. Piazza","doi":"10.1158/0008-5472.can-24-0323","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0323","url":null,"abstract":"RAS is a common driver of cancer that was considered undruggable for decades. Recent advances have enabled the development of RAS inhibitors, but the efficacy of these inhibitors remains limited by resistance. Here, we developed a pan-RAS inhibitor, ADT-007, that binds nucleotide-free RAS to block GTP activation of effector interactions and MAPK/AKT signaling, resulting in mitotic arrest and apoptosis. ADT-007 potently inhibited the growth of RAS mutant cancer cells irrespective of the RAS mutation or isozyme, and RASWT cancer cells with GTP-activated RAS from upstream mutations were equally sensitive. Conversely, RASWT cancer cells harboring downstream BRAF mutations and normal cells were essentially insensitive to ADT-007. Sensitivity of cancer cells to ADT-007 required activated RAS and dependence on RAS for proliferation, while insensitivity was attributed to metabolic deactivation by UDP-glucuronosyltransferases that were expressed in RASWT and normal cells but repressed in RAS mutant cancer cells. ADT-007 displayed unique advantages over KRAS mutant-specific, pan-KRAS, and pan-RAS inhibitors that could impact in vivo antitumor efficacy by escaping compensatory mechanisms that lead to resistance. Local administration of ADT-007 showed robust antitumor activity in syngeneic immune-competent and xenogeneic immune-deficient mouse models of colorectal and pancreatic cancer. The antitumor activity of ADT-007 was associated with the suppression of MAPK signaling and activation of innate and adaptive immunity in the tumor immune microenvironment. Oral administration of ADT-007 prodrug also inhibited tumor growth. Thus, ADT-007 has the potential to address the complex RAS mutational landscape of many human cancers and to improve treatment of RAS-driven tumors.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"29 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CLK1 Activates YAP to Promote Intrahepatic Cholangiocarcinogenesis","authors":"Shuai Xue, Xiangzheng Chen, Guoteng Qiu, Haotian Liao, Zeyuan Qiang, Zheng Zhang, Xuping Feng, Lin Xu, Rui Xie, Hongyu Zhou, Jiwei Huang, Yong Zeng, Haichuan Wang","doi":"10.1158/0008-5472.can-24-0147","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0147","url":null,"abstract":"Cdc2-like kinase 1 (CLK1) has dual-specificity kinase ability to phosphorylate tyrosine and serine/threonine protein residues. CLK1 regulates many physiological processes and has been shown to contribute to multiple types of cancer. Here, we investigated the functional role of CLK1 during intrahepatic cholangiocarcinoma (ICC) development. The expression of CLK1 was elevated in ICC tumors, and patients with high expression of CLK1 demonstrated poor prognosis. In hydrodynamically transfected mouse models, CLK1 alone was insufficient to induce ICC, whereas CLK1 cooperated with AKT (AKT/CLK1) to trigger ICC initiation. In addition, overexpression of CLK1 in ICC cells facilitated proliferation in vitro and tumor growth in vivo, while loss of CLK1 elicited the opposite effects. Moreover, RNAseq analysis indicated that high levels of CLK1 corresponded with activation of the Hippo-YAP signaling pathway. Consistently, the AKT/CLK1 murine tumors displayed upregulation of YAP as well as its downstream targets. Furthermore, loss or pharmacological inhibition YAP in ICC cells inhibited CLK1-induced growth, and deletion of Yap completely retarded the induction of AKT/CLK1 tumors. Mechanistically, 4D-label free mass spectrometry and co-immunoprecipitation assays revealed WWC2 as a potential mediator of CLK1-YAP cascade. Collectively, the current findings identify a critical role for CLK1 in promoting ICC development and indicate that inhibiting YAP might be an effective approach for perturbing CLK1-mediated tumorigenesis.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"109 21 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibody-Drug Conjugates Targeting the EGFR Ligand Epiregulin Elicit Robust Anti-Tumor Activity in Colorectal Cancer","authors":"Joan Jacob, Yasuaki Anami, Peyton C. High, Zhengdong Liang, Shraddha Subramanian, Sukhen C. Ghosh, Solmaz AghaAmiri, Cara Guernsey-Biddle, Ha Tran, Julie Rowe, Ali Azhdarinia, Kyoji Tsuchikama, Kendra S. Carmon","doi":"10.1158/0008-5472.can-24-0798","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0798","url":null,"abstract":"As colorectal cancer (CRC) remains a leading cause of cancer-related death, identifying therapeutic targets and approaches is essential to improve patient outcomes. The EGFR ligand epiregulin (EREG) is highly expressed in RAS wildtype and mutant CRC with minimal expression in normal tissues, making it an attractive target for antibody-drug conjugate (ADC) development. In this study, we produced and purified an EREG monoclonal antibody (mAb), H231, that had high specificity and affinity for human and mouse EREG. H231 also internalized to lysosomes, which is important for ADC payload release. ImmunoPET and ex vivo biodistribution studies showed significant tumor uptake of 89Zr-labeled H231 with minimal uptake in normal tissues. H231 was conjugated to either cleavable dipeptide or tripeptide chemical linkers attached to the DNA-alkylating payload duocarmycin DM, and cytotoxicity of EREG ADCs was assessed in a panel of CRC cell lines. EREG ADCs incorporating tripeptide linkers demonstrated the highest potency in EREG-expressing CRC cells irrespective of RAS mutations. Preclinical safety and efficacy studies showed EREG ADCs were well-tolerated, neutralized EGFR pathway activity, caused significant tumor growth inhibition or regression, and increased survival in CRC cell line and patient-derived xenograft models. These data suggest EREG is a promising target for the development of ADCs for treating CRC and other cancer types that express high levels of EREG. While the efficacy of clinically approved anti-EGFR mAbs are largely limited by RAS mutational status, EREG ADCs may show promise for both RAS mutant and wildtype patients, thus improving existing treatment options.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":"260 1","pages":""},"PeriodicalIF":11.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective Enhancer Gain-of-Function Deregulates MYC Expression in Multiple Myeloma.","authors":"Mahshid Rahmat, Kendell Clement, Jean-Baptiste Alberge, Romanos Sklavenitis-Pistofidis, Rohan Kodgule, Charles P Fulco, Daniel Heilpern-Mallory, Katarina Nilsson, David Dorfman, Jesse M Engreitz, Gad Getz, Luca Pinello, Russell J H Ryan, Irene M Ghobrial","doi":"10.1158/0008-5472.CAN-24-1440","DOIUrl":"10.1158/0008-5472.CAN-24-1440","url":null,"abstract":"<p><p>MYC deregulation occurs in the majority of multiple myeloma cases and is associated with progression and worse prognosis. Enhanced MYC expression occurs in about 70% of patients with multiple myeloma, but it is known to be driven by translocation or amplification events in only ∼40% of myelomas. Here, we used CRISPR interference to uncover an epigenetic mechanism of MYC regulation whereby increased accessibility of a plasma cell-type-specific enhancer leads to increased MYC expression. This native enhancer activity was not associated with enhancer hijacking events but led to specific binding of cMAF, IRF4, and SPIB transcription factors that activated MYC expression in the absence of known genetic aberrations. In addition, focal amplification was another mechanism of activation of this enhancer in approximately 3.4% of patients with multiple myeloma. Together, these findings define an epigenetic mechanism of MYC deregulation in multiple myeloma beyond known translocations or amplifications and point to the importance of noncoding regulatory elements and their associated transcription factor networks as drivers of multiple myeloma progression. Significance: The discovery of a native developmental enhancer that sustains the expression of MYC in a subset of myelomas could help identify predictive biomarkers and therapeutic targets to improve the outcomes of patients with multiple myeloma.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"4173-4183"},"PeriodicalIF":12.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting SHCBP1 Inhibits Tumor Progression by Restoring Ciliogenesis in Ductal Carcinoma.","authors":"Wengui Shi, Lianshun Li, Huiming Zhao, Zhengyang Li, Zhijian Ma, Qianlin Gu, Huili Ye, Xiangyan Jiang, Yuman Dong, Long Qin, Huinian Zhou, Zeyuan Yu, Zuoyi Jiao","doi":"10.1158/0008-5472.CAN-24-1095","DOIUrl":"10.1158/0008-5472.CAN-24-1095","url":null,"abstract":"<p><p>Primary cilia detect and transmit environmental signals into cells. Primary cilia are absent in a subset of ductal carcinomas characterized by distinctive biological activities, and recovery of cilia with normal functionality has been shown to have therapeutic potential in some cancer types. Therefore, elucidation of the underlying mechanism and clinical significance of ciliary loss in ductal carcinomas could help develop effective treatment strategies. Here, we identified a link between Shc1-binding protein (SHCBP1) and cilia in ductal carcinomas. Shcbp1 knockout in transgenic mice profoundly impeded tumor progression and metastasis, prolonging survival. Single-cell transcriptome analysis revealed a functional connection between SHCBP1 deficiency and increased tumor ciliogenesis. SHCBP1 ablation restored ciliogenesis in unciliated ductal carcinoma by promoting the proximity between the midbody remnant (MBR) and centrosome through enhanced Rab8 GTPase activity and Rab8GTP positioning within the MBR. Inhibition of tumor progression by SHCBP1 loss relied on the recovery of ciliogenesis. Analysis of a large cohort of patients with ductal carcinoma revealed a negative correlation between SHCBP1-induced ciliary loss and patient prognosis. Restoring ciliogenesis via SHCBP1 ablation elicited therapeutic effects in patient-derived xenograft models. Together, this study delineates that induction of MBR-centrosome proximity through SHCBP1-deficiency reactivates ciliogenesis, offering unique opportunities for the treatment of unciliated ductal carcinomas. Significance: SHCBP1 depletion rescues tumor ciliogenesis by enhancing Rab8 GTPase activity to restore the proximity of the  midbody remnant to the centrosome, which impedes progression of ductal carcinomas and suggests potential therapeutic strategies.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"4156-4172"},"PeriodicalIF":12.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Innate Immune System and the TRAIL-Bcl-XL Axis Mediate a Sex Bias in Lung Cancer and Confer a Therapeutic Vulnerability in Females.","authors":"Lauren May, Bin Hu, Preksha Jerajani, Akash Jagdeesh, Ohud Alhawiti, Lillian Cai, Nina Semenova, Chunqing Guo, Madison Isbell, Xiaoyan Deng, Anthony C Faber, Raghavendra Pillappa, Dipankar Bandyopadhyay, Xiang-Yang Wang, Alexander Neuwelt, Jennifer Koblinski, Paula D Bos, Howard Li, Rebecca Martin, Joseph W Landry","doi":"10.1158/0008-5472.CAN-24-0585","DOIUrl":"10.1158/0008-5472.CAN-24-0585","url":null,"abstract":"<p><p>There is a significant sex bias in lung cancer, with males showing increased mortality compared with females. A better mechanistic understanding of these differences could help identify therapeutic targets to personalize cancer therapies to each sex. After observing a clear sex bias in humanized mice, with male patient-derived xenograft lung tumors being more progressive and deadlier than female patient-derived xenograft lung tumors, we identified mouse tumor models of lung cancer with the same sex bias. This sex bias was not observed in models of breast, colon, melanoma, and renal cancers. In vivo, the sex bias in growth and lethality required intact ovaries, functional innate NK cells and monocytes/macrophages, and the activating receptor NKG2D. Ex vivo cell culture models were sensitized to the anticancer effects of NKG2D-mediated NK cell and macrophage killing through the TRAIL-Bcl-XL axis when cultured with serum from female mice with intact ovaries. In both flank and orthotopic models, the Bcl-XL inhibitor navitoclax (ABT-263) improved tumor growth control in female mice and required NK cells, macrophages, and the TRAIL signaling pathway. This research suggests that navitoclax and TRAIL pathway agonists could be used as a personalized therapy to improve outcomes in women with lung cancer. Significance: Lung cancers in females are more susceptible to killing through a TRAIL-Bcl-XL axis, indicating that targeting this axis therapeutically could represent a personalized approach to treat female patients with lung cancer.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"4140-4155"},"PeriodicalIF":12.5,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}