Chemotherapy rewires a novel resistance-promoting signaling pathway in ovarian cancer
Researchers from Karolinska Institutet along with clinicians from the Karolinska University Hospital have discovered a new molecular mechanism of cell oncogenic signaling switch, which is induced by platinum chemotherapy and contributes to treatment resistance in ovarian cancer.
Even with continuous development of new anti-cancer treatments, chemotherapy is used as the standard of care for many advanced cancers. However, the effects of chemotherapy on the cancer cell signaling and communication with their surrounding microenvironment, which could contribute to the recurrence of progressively resistant disease, remain incompletely understood.
One of the receptors that the cancer cells use to communicate with their microenvironment is EphA2. This receptor tyrosine kinase can be activated by interaction with ephrin ligands to elicit canonical, typically tumor-suppressive signaling, or by crosstalk with other kinases to promote oncogenic signaling. EphA2 is overexpressed in several cancer types, including ovarian high-grade serous cancer (HGSC), the most common and lethal form of ovarian cancer.
In a new study published in EMBO Molecular Medicine, the research group led by Kaisa Lehti identified a switch from the tumor-suppressive to the oncogenic EphA2 signaling, which is induced upon treatment of HGSC cells with platinum chemotherapy and associates with increased treatment resistance. Moreover, inhibitors against RSK1/2, the kinases mediating this oncogenic signaling, in combination with platinum efficiently sensitized cells to the chemotherapy-induced apoptosis in HGSC 2D and 3D models ex vivo as well as in vivo, presenting a novel approach of how to improve currently available platinum-based therapy for HGSC.
The first author, PhD student Lidia Moyano Galceran, in collaboration with researchers from Karolinska Institutet and Hospital, University of Helsinki (Finland) and Osaka City University Graduate School of Medicine (Japan), further discovered unique functions of RSK1/2 in the regulation of the EphA2 interacting G-protein coupled receptor, GPRC5A, likewise involved in sensing the microenvironment of the cancer cells. In HGSC patients, this receptor, previously uncharacterized in HGSC, was discovered to be a maker for poor survival and chemotherapy resistance. These are promising results that warrant future studies to investigate the potential of targeting the platinum-induced RSK-EphA2-GPRC5A signaling axis for improved tumor eradication.
The study was funded by Karolinska Institutet, the KI Strategic Research Program in Cancer (StratCan-KICancer), the Swedish Cancer Society, the Swedish Research Council, the Cancer Research Foundations of Radiumhemmet, as well as the Finnish Cancer Foundation and the Doctoral Program in Integrative Life Science.
“Adaptive RSK-EphA2-GPRC5A signaling switch triggers chemotherapy resistance in ovarian cancer”, Lidia Moyano-Galceran, Elina A Pietilä, S Pauliina Turunen, Sara Corvigno, Elisabet Hjerpe, Daria Bulanova, Ulrika Joneborg, Twana Alkasalias, Yuichiro Miki, Masakazu Yashiro, Anastasiya Chernenko, Joonas Jukonen, Madhurendra Singh, Hanna Dahlstrand, Joseph W Carlson, Kaisa Lehti, EMBO Molecular Medicine (2020).