Activated MKK3/MYC crosstalk impairs dabrafenib response in BRAFV600E colorectal cancer leading to resistance.

Autor: Pranteda A; Translational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy; Department of Science, University Roma TRE, Viale G. Marconi, 446 I, 00146 Rome, Italy., Piastra V; Translational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy; Department of Science, University Roma TRE, Viale G. Marconi, 446 I, 00146 Rome, Italy., Serra M; Interdepartmental Centre for Comparative Medicine, Alternative Techniques and Aquaculture (CIMETA), University of Rome 'Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy., Bernardini R; Interdepartmental Centre for Comparative Medicine, Alternative Techniques and Aquaculture (CIMETA), University of Rome 'Tor Vergata, Via Montpellier, 1, 00133 Rome, Italy; Center for Research and Services 'Preclinical Experimentation and Animal Welfare' (SPBA), University of Rome 'La Sapienza', Piazzale Aldo Moro, 5, 00185 Rome, Italy., Lo Sardo F; Translational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy., Carpano S; Second Division of Medical Oncology, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy., Diodoro MG; Department of Pathology, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy., Bartolazzi A; Pathology Research Laboratory, Sant'Andrea University Hospital, Via di Grottarossa, 1035, 00189 Rome, Italy., Milella M; UOC of Oncology, Verona University and Hospital Trust (Azienda Ospedaliera Universitaria Integrata-AOUI-Verona), Piazzale Aristide Stefani, 1, 37126 Verona, Italy., Blandino G; Translational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy., Bossi G; Translational Oncology Research Unit, Department of Diagnostic Research and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Via Elio Chianesi, 53, 00144 Rome, Italy. Electronic address: gianluca.bossi@ifo.it.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2023 Nov; Vol. 167, pp. 115480. Date of Electronic Publication: 2023 Sep 15.
DOI: 10.1016/j.biopha.2023.115480
Abstrakt: Colorectal cancer (CRC) patients with BRAF mutations develop resistance to BRAF inhibitors at a very early stage. Understanding the molecular mechanisms involved in BRAF inhibitor resistance is critical for the development of novel therapeutic opportunities for this subtype of CRC patients. CRC cells bearing BRAF mutations are mostly sensitive to the abrogation of Mitogen-Activated Protein Kinase Kinase 3 (MKK3), a specific activator of p38MAPKs signaling, suggesting that BRAF alterations might addict CRC cells to the MKK3/p38MAPK signaling. Interestingly, publicly available gene expression profiling data show significantly higher MKK3 transcript levels in CRC lines with acquired resistance to BRAF inhibitors. Herein, we investigated the roles of MKK3 in the response to BRAF targeting (dabrafenib) with COLO205 and HT29 BRAF V600E CRC lines and derived dabrafenib-resistant (DABR) sublines. Dabrafenib treatments reduce MKK3 activation by inducing autophagy in parental but not DABR cells. The MKK3 knockdown induces cell death in DABR cells, whereas ectopic MKK3 expression reduces dabrafenib sensitivity in parental cells. Mechanistically, activated MKK3 interacts and co-localizes with c-Myc oncoprotein (MYC), sustaining MYC protein stability and thus preventing the dabrafenib induced effects in CRC DABR cells both in vitro and in vivo. Overall, we identify a novel molecular mechanism beyond the dabrafenib resistance, shedding light on an uncovered vulnerability for the development of novel therapeutic opportunities in BRAF V600E CRC.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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