卵巢癌是妇科恶性肿瘤中的主要死亡原因。目前，检查点阻断免疫疗法在卵巢癌中的疗效仅显示出适度的效力，铂类化疗仍然是一线治疗。铂类抗药性的发展是导致卵巢癌复发和死亡的最重要因素之一。通过基因组宽度合成致死RNAi筛选结合细胞系铂反应数据库的无偏datamining，我们报道了没有胞外C末端调节酪氨酸和N末端肌醇化位点的Src-Related Kinase（SRMS），一种非受体酪氨酸激酶，是一种新型的MKK4-JNK信号的负调节因子在铂处理下发挥重要作用，对卵巢癌的铂效力起重要作用。特异抑制SRMS会使p53缺陷的卵巢癌细胞对铂感受性增加。机理上，SRMS作为铂诱导ROS的“传感器”。铂治疗引起的ROS激活SRMS，该ATP酪氨酸酶通过直接磷酸化MKK4的Y269和Y307抑制MKK4的激酶活性，从而抑制MKK4-JNK的激活。抑制SRMS会通过抑制MCL1转录来增强MKK4-JNK介导的细胞凋亡，从而提高铂的治疗效果。重要的是，通过一种“药物再利用”的策略，我们发现PLX4720，一种选择性B-RafV600E小分子抑制剂，是一种新型的SRMS抑制剂，可在卵巢癌体外和体内强力促进铂的效力。因此，以PLX4720作为SRMS的靶点有望提高铂类化疗的效果，并克服卵巢癌的化疗耐药性。©2023年 作者以Springer Nature Limited的独家许可发表。

Ovarian cancer is the leading cause of death among gynecological malignancies. Checkpoint blockade immunotherapy has so far only shown modest efficacy in ovarian cancer and platinum-based chemotherapy remains the front-line treatment. Development of platinum resistance is one of the most important factors contributing to ovarian cancer recurrence and mortality. Through kinome-wide synthetic lethal RNAi screening combined with unbiased datamining of cell line platinum response in CCLE and GDSC databases, here we report that Src-Related Kinase Lacking C-Terminal Regulatory Tyrosine And N-Terminal Myristylation Sites (SRMS), a non-receptor tyrosine kinase, is a novel negative regulator of MKK4-JNK signaling under platinum treatment and plays an important role in dictating platinum efficacy in ovarian cancer. Suppressing SRMS specifically sensitizes p53-deficient ovarian cancer cells to platinum in vitro and in vivo. Mechanistically, SRMS serves as a "sensor" for platinum-induced ROS. Platinum treatment-induced ROS activates SRMS, which inhibits MKK4 kinase activity by directly phosphorylating MKK4 at Y269 and Y307, and consequently attenuates MKK4-JNK activation. Suppressing SRMS leads to enhanced MKK4-JNK-mediated apoptosis by inhibiting MCL1 transcription, thereby boosting platinum efficacy. Importantly, through a "drug repurposing" strategy, we uncovered that PLX4720, a small molecular selective inhibitor of B-RafV600E, is a novel SRMS inhibitor that can potently boost platinum efficacy in ovarian cancer in vitro and in vivo. Therefore, targeting SRMS with PLX4720 holds the promise to improve the efficacy of platinum-based chemotherapy and overcome chemoresistance in ovarian cancer.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.