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

Iris Car1, Antje Dittmann2, Olga Vasieva3

  • 1Centre for Applied Bioanthropology, Institute for Anthropological Research, Ljudevita Gaja 32, 10000 Zagreb, Croatia.

International Journal of Molecular Sciences
|August 26, 2023
PubMed

Insights

Ezrin protein contributes to resistance against BRAFV600E inhibitors like vemurafenib in colorectal cancer and melanoma. Inhibiting ezrin alongside vemurafenib may improve treatment outcomes for these BRAF-mutated cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Proteomics

Background:

  • Targeted therapies for BRAFV600E-mutated metastatic colorectal cancer (mCRC) show promise but are limited by acquired resistance.
  • Understanding resistance mechanisms is crucial for developing effective pharmacological strategies against BRAF-mutated mCRC.

Purpose of the Study:

  • To identify novel protein candidates involved in acquired resistance to the BRAFV600E inhibitor vemurafenib in BRAFV600E-mutated colon cancer cells.
  • To investigate the role of identified proteins in vemurafenib resistance in both colon cancer and melanoma models.

Main Methods:

  • Integrated proteomics approach to analyze protein expression in vemurafenib-resistant colon cancer cells.
  • Bioinformatic analysis to identify significantly associated proteins.
  • Gene and protein level validation of ezrin expression.
  • Pharmacological inhibition of ezrin and assessment of its effects on vemurafenib sensitivity, cell proliferation, apoptosis, CD44 expression, and AKT/c-Myc signaling.
  • Evaluation of ezrin's role in vemurafenib-resistant melanoma cells.

Main Results:

  • Proteomics identified ezrin, an actin-cytoskeleton linker protein, as significantly associated with vemurafenib resistance.
  • Ezrin overexpression was confirmed in resistant colon cancer cells at both gene and protein levels.
  • Ezrin inhibition, using NSC305787, enhanced vemurafenib's anti-proliferative and pro-apoptotic effects in resistant colon cancer cells additively, with decreased CD44, AKT, and c-Myc.
  • Increased ezrin expression was also observed in vemurafenib-resistant melanoma cells with BRAFV600E mutation.
  • Ezrin inhibition synergistically potentiated vemurafenib's anti-proliferative and pro-apoptotic effects in resistant melanoma cells.

Conclusions:

  • Ezrin plays a role in acquired resistance to vemurafenib in BRAFV600E-mutated colon cancer and melanoma.
  • Combined inhibition of BRAF inhibitors and ezrin (actin-targeting drugs) represents a potential therapeutic strategy for BRAFV600E-mutated cancers.
  • Further pre-clinical and clinical studies are warranted to explore this combined therapeutic approach.
Keywords:
BRAF inhibitorBRAFV600ENSC305787actin cytoskeletoncolon cancerezrinezrin inhibitormelanomavemurafenib

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