Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer

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Lidia Moyano-Galceran; Elina A Pietilä; Kaisa Lehti

doi:10.15252/emmm.201911177

Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. However, the contribution of chemotherapy itself to the non-genetic resistance mechanisms was long neglected. Using high-grade serous ovarian cancer (HGSC) patient material and cell lines, we describe here an unexpectedly robust cisplatin and carboplatin chemotherapy-induced ERK1/2-RSK1/2-EphA2-GPRC5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK1/2 prevented oncogenic EphA2-S897 phosphorylation and EphA2-GPRC5A co-regulation, thereby facilitating a signaling shift to the canonical tumor-suppressive tyrosine phosphorylation and consequent downregulation of EphA2. In combination with platinum, RSK inhibitors effectively sensitized even the most platinum-resistant EphA2

Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer

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