Despite increased understanding of chemotherapy resistance, the effects of the chemotherapy itself on the oncogenic cancer cell properties and adaptive resistance mechanisms of the therapy-escaping metastatic cancer cells remain largely undefined. In this study, we show that the platinum-based chemotherapeutic drugs cisplatin and carboplatin induce a switch from the canonical EphA2 receptor tyrosine kinase activity to the stemness and invasion-associated, ligand independent signaling via EphA2 S897 phosphorylation. In patient-derived high grade serous ovarian cancer (HGSOC) cells and established ovarian cancer cell lines, the chemotherapy treatment led to a significant increase in the ratio between S897 and Y588 phosphorylation of EphA2 in conjunction with GPRC5A protein upregulation and beta1-integrin activation. Notably, high protein levels of GPRC5A were significantly associated to poor survival in patients with metastatic HGSOC, revealing a previously unknown association of this EphA2 interacting receptor with the clinical HGSOC outcome. Moreover, pharmacological inhibition of RSK serine-threonine kinases blocked both the EphA2 S897 phosphorylation and the GPRC5A induction coincident with markedly increased cisplatin and carboplatin sensitivity of the HGSOC cells ex vivo. These results identify a novel mechanism of chemotherapy-induced adaptive resistance via the RSK-EphA2-GPRC5A oncogenic signaling axis in HGSOC.

Citation Format: Lidia Moyano-Galceran, Siri Pauliina Turunen, Elina Pietilä, Twana Alkasalias, Sara Corvigno, Elisabet Hjerpe, Ulrika Joneborg, Daria Bulanova, Mina Eriksson, Hanna Dahlstrand, Joseph Carlson, Kaisa Lehti. OVARIAN CANCER CELLS INDUCE A FEEDBACK RESPONSE TO PLATINUM-BASED CHEMOTHERAPY BY ACTIVATING AN ONCOGENIC RSK-EPHA2-GPRC5A SIGNALING SWITCH [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-041.