Novel protein kinase signaling associated with platinum resistance in ovarian cancer

点击翻译按钮获取中文摘要

PROJECT SUMMARY Development of platinum resistance is one of the most important factors contributing to ovarian cancer recurrence and mortality. In our effort to decipher molecular mechanisms underlying platinum resistance, we performed a kinome-wide screening on platinum-resistant SK-OV3 ovarian cancer cell line and identified Src- Related Kinase Lacking C-Terminal Regulatory Tyrosine And N-Terminal Myristylation Sites (SRMS) as a top platinum resistance regulator. Further analysis of TCGA ovarian cancer dataset revealed that patients with high SRMS expression responded poorly to platinum-based therapy and had worse overall survival. Since knockdown of SRMS markedly sensitized p53-deficient ovarian cancer cell lines to platinum while only displayed minor effect on p53-competent cell lines, we reason that SRMS plays a critical role in platinum resistance of p53-deficient ovarian cancer. To glean the mechanistic insight into the role of SRMS in platinum resistance, we showed that SRMS prevents JNK activation, possibly by directly phosphorylating JNKs. JNK signaling pathway is well established as an essential mediator for apoptosis triggered by cytotoxic agents; our observation that SRMS is specifically involved in platinum resistance in p53-deficient cells suggests that 1) platinum induces apoptosis in p53-deficient ovarian cancer cells in a JNK signaling pathway-dependent manner because of the defect in p53 signaling pathway-mediated apoptosis; and 2) SRMS-led inhibition of JNK signaling alleviates platinum-induced apoptosis and thereby promotes platinum resistance in p53-deficient cells. p53 is uniformly deficient in high grade serous ovarian cancer (HGSOC). The discovery of SRMS’ prominent role in platinum resistance of p53- deficient cells indicates that SRMS can be an ideal therapeutic target against platinum resistance in HGSOC. In our “drug repurposing” screening, we found that PLX4720, a selective inhibitor of B-RafV600E, can potently inhibit SRMS activity. In this application, we propose 3 specific aims: 1) Characterize molecular mechanisms underlying SRMS-conferred platinum resistance; 2) Define platinum resistance-relevant events that are governed by SRMS-JNK signaling; and 3) Investigate the potential of targeting SRMS to augment efficacy of platinum therapy. The success of this application will uncover molecular mechanism underlying SRMS’ role in platinum resistance of ovarian cancer. Importantly, we will evaluate SRMS-targeted strategy to overcome platinum resistance in ovarian cancer.