Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer

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http://hdl.handle.net/10138/315190

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Moyano-Galceran , L , Pietila , E A , Turunen , S P , Corvigno , S , Hjerpe , E , Bulanova , D , Joneborg , U , Alkasalias , T , Miki , Y , Yashiro , M , Chernenko , A , Jukonen , J , Singh , M , Dahlstrand , H , Carlson , J W & Lehti , K 2020 , ' Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer ' , EMBO molecular medicine , vol. 12 , no. 4 , 11177 . https://doi.org/10.15252/emmm.201911177

Title: Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer
Author: Moyano-Galceran, Lidia; Pietila, 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
Contributor: University of Helsinki, INDIVIDRUG - Individualized Drug Therapy
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, INDIVIDRUG - Individualized Drug Therapy
University of Helsinki, INDIVIDRUG - Individualized Drug Therapy
University of Helsinki, INDIVIDRUG - Individualized Drug Therapy
Date: 2020-04
Number of pages: 22
Belongs to series: EMBO molecular medicine
ISSN: 1757-4676
URI: http://hdl.handle.net/10138/315190
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 EphA2(high), GPRC5A(high) 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.
Subject: chemotherapy
EphA2
GPRC5A
HGSC
resistance
TO-MESENCHYMAL TRANSITION
1ST-LINE TREATMENT
TUMOR-SUPPRESSOR
BREAST-CANCER
DOUBLE-BLIND
EPHA2
INVASION
HETEROGENEITY
METASTASIS
MECHANISMS
3122 Cancers
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