Ezrin Inhibition Overcomes Acquired Resistance to Vemurafenib in BRAFV600E-Mutated Colon Cancer and Melanoma Cells In Vitro

Car, Iris; Dittmann, Antje; Vasieva, Olga; Bočkor, Luka; Grbčić, Petra; Piteša, Nikolina; Klobučar, Marko; Kraljević Pavelić, Sandra; Sedić, Mirela (2023) Ezrin Inhibition Overcomes Acquired Resistance to Vemurafenib in BRAFV600E-Mutated Colon Cancer and Melanoma Cells In Vitro. International Journal of Molecular Sciences, 24 (16). ISSN 1422-0067

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Abstract

Despite the advancements in targeted therapy for BRAFV600E-mutated metastatic colorectal cancer (mCRC), the development of resistance to BRAFV600E inhibition limits the response rate and durability of the treatment. Better understanding of the resistance mechanisms to BRAF inhibitors will facilitate the design of novel pharmacological strategies for BRAF-mutated mCRC. The aim of this study was to identify novel protein candidates involved in acquired resistance to BRAFV600E inhibitor vemurafenib in BRAFV600E-mutated colon cancer cells using an integrated proteomics approach. Bioinformatic analysis of obtained proteomics data indicated actin-cytoskeleton linker protein ezrin as a highly ranked protein significantly associated with vemurafenib resistance whose overexpression in the resistant cells was additionally confirmed at the gene and protein level. Ezrin inhibition by NSC305787 increased anti-proliferative and pro-apoptotic effects of vemurafenib in the resistant cells in an additive manner, which was accompanied by downregulation of CD44 expression and inhibition of AKT/c-Myc activities. We also detected an increased ezrin expression in vemurafenib-resistant melanoma cells harbouring the BRAFV600E mutation. Importantly, ezrin inhibition potentiated anti-proliferative and pro-apoptotic effects of vemurafenib in the resistant melanoma cells in a synergistic manner. Altogether, our study suggests a role of ezrin in acquired resistance to vemurafenib in colon cancer and melanoma cells carrying the BRAFV600E mutation and supports further pre-clinical and clinical studies to explore the benefits of combined BRAF inhibitors and actin-targeting drugs as a potential therapeutic approach for BRAFV600E-mutated cancers.

Item Type:	Article
Uncontrolled Keywords:	BRAFV600E; colon cancer; melanoma; BRAF inhibitor; vemurafenib; ezrin; actin cytoskeleton; ezrin inhibitor; NSC305787
Subjects:	BIOMEDICINE AND HEALTHCARE
Divisions:	Division of Molecular Medicine
Projects:	Project title Project leader Project code Project type Rasvijetljavanje mehanizama rezistencije na terapiju raka debelog crijeva sa mutacijom BRAF pomoću integriranog -omics pristupa-BRAFCON Mirela Sedić IP-2018-01-3900 HRZZ
Depositing User:	Ema Buhin Šaler
Date Deposited:	23 Mar 2026 10:01
URI:	http://fulir.irb.hr/id/eprint/11399
DOI:	10.3390/ijms241612906

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