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.

中文翻译：

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靶向 PREX2/RAC1/PI3Kβ 信号轴赋予对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主要的临床挑战。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，这些突变与对 BRAF 靶向治疗的耐药性有关。靶向 RAC1-GTP 酶通路，包括上游激活剂 PREX2 和下游效应物 PI3Kβ，可能是克服治疗耐药性、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剖析 PREX2 在黑色素瘤发生和对治疗反应中的作用。虽然 PREX2 对于黑色素瘤的发生和进展是可有可无的，但它的缺失赋予了对靶向 MAPK 通路的临床相关疗法的敏感性。重要的是，PI3Kβ 表型复制 PREX2 缺陷的遗传和药理学靶向，使模型系统对治疗敏感。这些数据揭示了 BRAF 突变黑色素瘤中的可成药 PREX2/RAC1/PI3Kβ 信号轴，可以在临床上开发。