Here, using established chemo‐sensitive and chemo‐resistant HGSC cell models in vitro and in vivo, as well as treatment‐naïve primary and early passage ex vivo cultures from HGSC patients, we uncovered a robust mechanism, whereby cancer cells gain platinum resistance via the treatment‐induced, adaptive RSK1/2‐EphA2‐GPRC5A signaling switch. The gene discussed is RPS6KA1; the disease is cancer.