Abstract
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 EphA2high, GPRC5Ahigh cells to the therapy‐induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo‐resistant cells to RSK1/2‐EphA2‐pS897 pathway inhibition.
Highlights
Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells
Cisplatin treatment leads to erythropoietin-producing hepatocellular receptor A2 (EphA2) upregulation in patientderived highgrade serous ovarian cancer (HGSC) cells ex vivo
Taken together with EphA2 upregulation after GPRC5A partial knockdown upon platinum treatment in TYK-nu, but not in TYK-nu.R (Appendix Fig S5A–C), these results suggest that EphA2 and GPRC5A are mutually negatively regulated in the platinum-sensitive cells
Summary
Metastatic cancers commonly activate adaptive chemotherapy resistance, attributed to both microenvironment-dependent phenotypic plasticity and genetic characteristics of cancer cells. Using highgrade 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. In HGSC patient tumors, this orphan receptor GPRC5A was expressed exclusively in cancer cells and associated with chemotherapy resistance and poor survival. Our results reveal a kinase signaling pathway uniquely activated by platinum to elicit adaptive resistance. They further identify GPRC5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemoresistant cells to RSK1/2-EphA2-pS897 pathway inhibition
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