Targeting the PREX2/RAC1/PI3Kβ Signaling Axis Confers Sensitivity to Clinically Relevant Therapeutic Approaches in Melanoma

IF 12.5 1区 医学 Q1 ONCOLOGY Cancer research Pub Date : 2024-12-05 DOI:10.1158/0008-5472.can-23-2814
Catriona A. Ford, Dana Koludrovic, Patricia P. Centeno, Mona Foth, Elpida Tsonou, Nikola Vlahov, Nathalie Sphyris, Kathryn Gilroy, Courtney Bull, Colin Nixon, Bryan Serrels, Alison F. Munro, John C. Dawson, Neil O. Carragher, Valeria Pavet, David C. Hornigold, Philip D. Dunne, Julian Downward, Heidi C. Welch, Simon T. Barry, Owen J. Sansom, Andrew D. Campbell
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Abstract

Metastatic melanoma remains a major clinical challenge. Large-scale genomic sequencing of melanoma has identified bona fide activating mutations in RAC1, which are associated with resistance to BRAF-targeting therapies. Targeting the RAC1-GTPase pathway, including the upstream activator PREX2 and the downstream effector PI3Kβ, could be a potential strategy for overcoming therapeutic resistance, limiting melanoma recurrence, and suppressing metastatic progression. Here, we used genetically engineered mouse models and patient-derived BRAFV600E-driven melanoma cell lines to dissect the role of PREX2 in melanomagenesis and response to therapy. While PREX2 was dispensable for the initiation and progression of melanoma, its loss conferred sensitivity to clinically relevant therapeutics targeting the MAPK pathway. Importantly, genetic and pharmacological targeting of PI3Kβ phenocopied PREX2 deficiency, sensitizing model systems to therapy. These data reveal a druggable PREX2/RAC1/PI3Kβ signaling axis in BRAF-mutant melanoma that could be exploited clinically.
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靶向PREX2/RAC1/PI3Kβ信号轴赋予黑色素瘤临床相关治疗方法的敏感性
转移性黑色素瘤仍然是一个重大的临床挑战。黑色素瘤的大规模基因组测序已经确定了RAC1中真正的激活突变,这与对braf靶向治疗的耐药性有关。靶向RAC1-GTPase通路,包括上游激活因子PREX2和下游效应因子PI3Kβ,可能是克服治疗耐药、限制黑色素瘤复发和抑制转移进展的潜在策略。在这里,我们使用基因工程小鼠模型和患者来源的brafv600e驱动的黑色素瘤细胞系来解剖PREX2在黑色素瘤发生和治疗反应中的作用。虽然PREX2在黑色素瘤的发生和发展中是不可缺少的,但它的缺失使其对针对MAPK通路的临床相关治疗具有敏感性。重要的是,PI3Kβ的遗传和药理学靶向表型PREX2缺陷,使模型系统对治疗敏感。这些数据揭示了braf突变黑色素瘤中可用药的PREX2/RAC1/PI3Kβ信号轴,可用于临床开发。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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