Department of Molecular Medicine, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
Department of Cell and Tissue Biology, School of Dentistry, University of California San Francisco, San Francisco, CA, 94143, USA.
Oncogene. 2023 May;42(20):1672-1684. doi: 10.1038/s41388-023-02679-6. Epub 2023 Apr 5.
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-RafV, 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.
卵巢癌是妇科恶性肿瘤死亡的主要原因。检查点阻断免疫疗法迄今为止在卵巢癌中仅显示出适度的疗效，而铂类化疗仍然是一线治疗。铂耐药的发展是导致卵巢癌复发和死亡的最重要因素之一。通过全激酶组合成致死 RNAi 筛选，结合 CCLE 和 GDSC 数据库中细胞系对铂反应的无偏 datamining，我们报告了非受体酪氨酸激酶 Src 相关激酶缺乏 C 端调节酪氨酸和 N 端豆蔻酰化位点（SRMS）是铂治疗下 MKK4-JNK 信号的新型负调节剂，在决定卵巢癌铂疗效方面发挥着重要作用。特异性抑制 SRMS 可在体外和体内使 p53 缺陷型卵巢癌细胞对铂敏感。从机制上讲，SRMS 是铂诱导 ROS 的“传感器”。铂处理诱导的 ROS 激活 SRMS，通过直接在 Y269 和 Y307 处磷酸化 MKK4 来抑制 MKK4 激酶活性，从而减弱 MKK4-JNK 激活。通过抑制 MCL1 转录，抑制 SRMS 会导致增强的 MKK4-JNK 介导的细胞凋亡，从而增强铂的疗效。重要的是，通过“药物再利用”策略，我们发现 PLX4720，一种 B-RafV 的小分子选择性抑制剂，是一种新型的 SRMS 抑制剂，可在体外和体内有力地增强卵巢癌的铂疗效。因此，用 PLX4720 靶向 SRMS 有望提高基于铂的化疗疗效并克服卵巢癌的化疗耐药性。
