Overexpression of Mcl-1 confers resistance to BRAFV600E inhibitors alone and in combination with MEK1/2 inhibitors in melanoma
Year: 2015
Type: article
Abstract: // Neel M. Fofaria 1 , Dennie T. Frederick 2, 3 , Ryan J. Sullivan 2, 3 , Keith T. Flaherty 2, 3 , Sanjay K. Srivastava 1 1 Department of Biomedical Sciences and Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, TX, USA 2 Harvard Medical School, Boston, Massachusetts, USA 3 Division of Medical Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA Correspondence to: Sanjay K. Srivastava, e-mail: [email protected] Keywords: BRAF inhibitors, de novo and acquired resistance, MEK1/2 inhibitors, Mcl-1, combination therapy Received: August 21, 2015 Accepted: September 20, 2015 Published: October 14, 2015 ABSTRACT Melanoma harboring BRAF mutations frequently develop resistance to BRAF inhibitors, limiting the impact of treatment. Here, we establish a mechanism of resistance and subsequently identified a suitable drug combination to overcome the resistance. Single treatment of BRAF mutant melanoma cell lines with vemurafenib or dabrafenib (BRAF inhibitors) alone or in combination with trametinib (MEK1/2 inhibitor) resulted in overexpression of Mcl-1. Overexpression of Mcl-1 in A375 and SK-MEL-28 by transfection completely blocked BRAF and MEK1/2 inhibitor-mediated inhibition of cell survival and apoptosis. Melanoma cells resistant to BRAF inhibitors showed massive expression of Mcl-1 as compared to respective sensitive cell lines. Silencing of Mcl-1 using siRNA completely sensitized resistant melanoma cells to growth suppression and induction of apoptosis by BRAF inhibitors. In vivo , vemurafenib resistant A375 xenografts implanted in athymic nude mice showed substantial tumor growth inhibition when treated with a combination of vemurafenib and Mcl-1 inhibitor or siRNA. Immunohistochemistry and western blot analyses demonstrated enhanced expression of Mcl-1 and activation of ERK1/2 in vemurafenib-resistant tumors whereas level of Mcl-1 or p-ERK1/2 was diminished in the tumors of mice treated with either of the combination. Biopsied tumors from the patients treated with or resistant to BRAF inhibitors revealed overexpression of Mcl-1. These results suggest that the combination of BRAF inhibitors with Mcl-1 inhibitor may have therapeutic advantage to melanoma patients with acquired resistance to BRAF inhibitors alone or in combination with MEK1/2 inhibitors.
Source: Oncotarget
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: diamond
Funder: National Cancer Institute
Awards: G307434437, G7647328856, G8946024073
OpenAlex ID: W1868879889