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ROS-mediated SRMS activation confers platinum resistance in ovarian cancer

Oncogene volume 42, pages 1672–1684 (2023)Cite this article

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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.

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Fig. 1: Identification of SRMS as a potential driver of platinum resistance in human ovarian cancer.
Fig. 2: Silencing SRMS sensitizes cisplatin treatment in vitro and in vivo.
Fig. 3: SRMS silencing promotes platinum-induced apoptosis.
Fig. 4: Silencing SRMS leads to hyper-activation of MKK4-JNK-c-Jun axis upon platinum treatment.
Fig. 5: SRMS directly phosphorylates MKK4 and inhibits MKK4-JNK-c-Jun activation upon platinum treatment.
Fig. 6: SRMS sustains MCL-1 gene transcription to confer platinum resistance.
Fig. 7: Characterization of pLX4720 as a potential SRMS inhibitor that can boost platinum efficacy in ovarian cancer cells in vitro and in vivo.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. RNA sequencing data has been deposited to GEO repository (GSE206226). Additional data related to this paper may be requested from the authors.

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Acknowledgements

We acknowledge Ryan Clay for editorial assistance.

Funding

This work was supported in part by NIH grants R37 CA249305 (LJ), R01CA269782 (LJ), R01 CA256482 (SH and LJ), DoD LCRP Career Development Award W81XWH2010309 (LJ), Lung Cancer Research Foundation pilot grant (LJ) and American Lung Association Innovation Award (LJ).

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Authors and Affiliations

  1. Department of Molecular Medicine, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA

    Yunhan Jiang, Lina Song, Pawel Nowialis, Qiongmei Gao & Lingtao Jin

  2. Department of Cell and Tissue Biology, School of Dentistry, University of California San Francisco, San Francisco, CA, 94143, USA

    Yizhu Lin

  3. Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL, 32610, USA

    Tao Li, Bin Li & Shuang Huang

  4. Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Xiaobo Mao

  5. Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27101, USA

    Qianqian Song

  6. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA

    Chengguo Xing & Guangrong Zheng

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Contributions

LJ and YJ conceived and designed this study. YJ performed all experiments with assistance from LS, PN, QG, TL, and LJ; BL provided critical reagents. YL performed analysis of RNA-sequencing data. XM, QS, CX, GZ, and SH provided experimental advices. LJ and YJ wrote the paper. LJ supervised the project.

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Correspondence to Lingtao Jin.

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Jiang, Y., Song, L., Lin, Y. et al. ROS-mediated SRMS activation confers platinum resistance in ovarian cancer. Oncogene 42, 1672–1684 (2023). https://doi.org/10.1038/s41388-023-02679-6

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