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. The gene discussed is RPS6KA1; the disease is ovarian serous adenocarcinoma.