{"id":1672,"date":"2023-04-27T13:01:14","date_gmt":"2023-04-27T18:01:14","guid":{"rendered":"https:\/\/lsom.uthscsa.edu\/molecular-medicine\/?p=1672"},"modified":"2023-04-27T13:07:23","modified_gmt":"2023-04-27T18:07:23","slug":"ros-mediated-srms-activation-confers-platinum-resistance-in-ovarian-cancer","status":"publish","type":"post","link":"https:\/\/lsom.uthscsa.edu\/molecular-medicine\/2023\/04\/27\/ros-mediated-srms-activation-confers-platinum-resistance-in-ovarian-cancer\/","title":{"rendered":"ROS-Mediated SRMS Activation Confers Platinum Resistance in Ovarian Cancer"},"content":{"rendered":"<p><strong>Abstract<\/strong><\/p>\n<p>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 \u201csensor\u201d 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 \u201cdrug repurposing\u201d 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.<\/p>\n<p>Yunhan Jiang, Lina Song, Yizhu Lin, Pawel Nowialis, Qiongmei Gao, Tao Li, Bin Li, Xiaobo Mao, Qianqian Song, Chengguo Xing, Guangrong Zheng, Shuang Huang, Lingtao Jin.<\/p>\n","protected":false},"excerpt":{"rendered":"<p>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 [&hellip;]<\/p>\n","protected":false},"author":315,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3],"class_list":["post-1672","post","type-post","status-publish","format-standard","hentry","category-highimpactpublication"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v28.5 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>ROS-Mediated SRMS Activation Confers Platinum Resistance in Ovarian Cancer - Department of Molecular Medicine<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/lsom.uthscsa.edu\/molecular-medicine\/2023\/04\/27\/ros-mediated-srms-activation-confers-platinum-resistance-in-ovarian-cancer\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"ROS-Mediated SRMS Activation Confers Platinum Resistance in Ovarian Cancer - Department of Molecular Medicine\" \/>\n<meta property=\"og:description\" content=\"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 [&hellip;]\" \/>\n<meta property=\"og:url\" content=\"https:\/\/lsom.uthscsa.edu\/molecular-medicine\/2023\/04\/27\/ros-mediated-srms-activation-confers-platinum-resistance-in-ovarian-cancer\/\" \/>\n<meta property=\"og:site_name\" content=\"Department of Molecular Medicine\" \/>\n<meta property=\"article:published_time\" content=\"2023-04-27T18:01:14+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2023-04-27T18:07:23+00:00\" \/>\n<meta name=\"author\" content=\"villelaj\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written by\" \/>\n\t<meta name=\"twitter:data1\" content=\"villelaj\" \/>\n\t<meta name=\"twitter:label2\" content=\"Est. reading time\" \/>\n\t<meta name=\"twitter:data2\" content=\"2 minutes\" \/>\n<script type=\"application\/ld+json\" class=\"yoast-schema-graph\">{\"@context\":\"https:\\\/\\\/schema.org\",\"@graph\":[{\"@type\":\"Article\",\"@id\":\"https:\\\/\\\/lsom.uthscsa.edu\\\/molecular-medicine\\\/2023\\\/04\\\/27\\\/ros-mediated-srms-activation-confers-platinum-resistance-in-ovarian-cancer\\\/#article\",\"isPartOf\":{\"@id\":\"https:\\\/\\\/lsom.uthscsa.edu\\\/molecular-medicine\\\/2023\\\/04\\\/27\\\/ros-mediated-srms-activation-confers-platinum-resistance-in-ovarian-cancer\\\/\"},\"author\":{\"name\":\"villelaj\",\"@id\":\"https:\\\/\\\/lsom.uthscsa.edu\\\/molecular-medicine\\\/#\\\/schema\\\/person\\\/046bc1eb7969c260f31ef491b2153f81\"},\"headline\":\"ROS-Mediated SRMS Activation Confers Platinum Resistance in Ovarian Cancer\",\"datePublished\":\"2023-04-27T18:01:14+00:00\",\"dateModified\":\"2023-04-27T18:07:23+00:00\",\"mainEntityOfPage\":{\"@id\":\"https:\\\/\\\/lsom.uthscsa.edu\\\/molecular-medicine\\\/2023\\\/04\\\/27\\\/ros-mediated-srms-activation-confers-platinum-resistance-in-ovarian-cancer\\\/\"},\"wordCount\":271,\"articleSection\":[\"High Impact Publications\"],\"inLanguage\":\"en-US\"},{\"@type\":\"WebPage\",\"@id\":\"https:\\\/\\\/lsom.uthscsa.edu\\\/molecular-medicine\\\/2023\\\/04\\\/27\\\/ros-mediated-srms-activation-confers-platinum-resistance-in-ovarian-cancer\\\/\",\"url\":\"https:\\\/\\\/lsom.uthscsa.edu\\\/molecular-medicine\\\/2023\\\/04\\\/27\\\/ros-mediated-srms-activation-confers-platinum-resistance-in-ovarian-cancer\\\/\",\"name\":\"ROS-Mediated SRMS Activation Confers Platinum Resistance in Ovarian Cancer - 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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. 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