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

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...

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Autores principales: Moyano‐Galceran, 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136956/
https://www.ncbi.nlm.nih.gov/pubmed/32115889
http://dx.doi.org/10.15252/emmm.201911177
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author Moyano‐Galceran, 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
author_facet Moyano‐Galceran, 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
author_sort Moyano‐Galceran, Lidia
collection PubMed
description 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.
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spelling pubmed-71369562020-04-08 Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer Moyano‐Galceran, 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 EMBO Mol Med Articles 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. John Wiley and Sons Inc. 2020-03-02 2020-04-07 /pmc/articles/PMC7136956/ /pubmed/32115889 http://dx.doi.org/10.15252/emmm.201911177 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Moyano‐Galceran, 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
Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer
title Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer
title_full Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer
title_fullStr Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer
title_full_unstemmed Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer
title_short Adaptive RSK‐EphA2‐GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer
title_sort adaptive rsk‐epha2‐gprc5a signaling switch triggers chemotherapy resistance in ovarian cancer
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136956/
https://www.ncbi.nlm.nih.gov/pubmed/32115889
http://dx.doi.org/10.15252/emmm.201911177
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