Faculty, Staff and Student Publications

Language

English

Publication Date

5-1-2023

Journal

Oncogene

DOI

10.1038/s41388-023-02679-6

PMID

37020040

PMCID

PMC10231978

PubMedCentral® Posted Date

11-1-2023

PubMedCentral® Full Text Version

Author MSS

Abstract

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.

Keywords

Humans, Female, Reactive Oxygen Species, Platinum, Cell Line, Tumor, Neoplasm Recurrence, Local, Ovarian Neoplasms, src-Family Kinases, Drug Resistance, Neoplasm, Indoles, Sulfonamides, Platinum-based chemotherapy, platinum resistance, SRMS, JNK, PLX4720

Published Open-Access

yes

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