Open AccessAdaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer
Author(s) -
MoyanoGalceran Lidia,
Pietilä Elina A,
Turunen S Pauliina,
Corvigno Sara,
Hjerpe Elisabet,
Bulanova Daria,
Joneborg Ulrika,
Alkasalias Twana,
Miki Yuichiro,
Yashiro Masakazu,
Chernenko Anastasiya,
Jukonen Joonas,
Singh Madhurendra,
Dahlstrand Hanna,
Carlson Joseph W,
Lehti Kaisa
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201911177
Subject(s) - ovarian cancer , cancer research , signal transduction , eph receptor a2 , chemotherapy , chemistry , medicine , microbiology and biotechnology , cancer , biology , receptor tyrosine kinase
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 ERK 1/2‐ RSK 1/2‐EphA2‐ GPRC 5A signaling switch associated with cancer cell intrinsic and acquired chemoresistance. Mechanistically, pharmacological inhibition or knockdown of RSK 1/2 prevented oncogenic EphA2‐S897 phosphorylation and EphA2‐ GPRC 5A 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 high , GPRC 5A high cells to the therapy‐induced apoptosis. In HGSC patient tumors, this orphan receptor GPRC 5A 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 GPRC 5A as a marker for abysmal HGSC outcome and putative vulnerability of the chemo‐resistant cells to RSK 1/2‐EphA2‐ pS 897 pathway inhibition.