MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB.

Clin Cancer Res 2016 Dec 11;22(24):6088-6098. Epub 2016 Aug 11.

Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.

Purpose: To determine if BRAF and/or MEK inhibitor-induced GPNMB expression renders melanomas sensitive to CDX-011, an antibody-drug conjugate targeting GPNMB.

Experimental Design: The Cancer Genome Atlas melanoma dataset was interrogated for a panel of MITF-regulated melanosomal differentiation antigens, including GPNMB. BRAF-mutant melanoma cell lines treated with BRAF or MEK inhibitors were assessed for GPNMB expression by RT-qPCR, immunoblot, and FACS analyses. Transient siRNA-mediated knockdown approaches were used to determine if MITF is requirement for treatment-induced GPNMB upregulation. GPNMB expression was analyzed in serial biopsies and serum samples from patients with melanoma taken before, during, and after disease progression on MAPK inhibitor treatment. Subcutaneous injections were performed to test the efficacy of MAPK inhibitors alone, CDX-011 alone, or their combination in suppressing melanoma growth.

Results: A MITF-dependent melanosomal differentiation signature is associated with poor prognosis in patients with this disease. MITF is increased following BRAF and MEK inhibitor treatment and induces the expression of melanosomal differentiation genes, including GPNMB. GPNMB is expressed at the cell surface in MAPK inhibitor-treated melanoma cells and is also elevated in on-treatment versus pretreatment biopsies from melanoma patients receiving MAPK pathway inhibitors. Combining BRAF and/or MEK inhibitors with CDX-011, an antibody-drug conjugate targeting GPNMB, is effective in causing melanoma regression in preclinical animal models and delays the recurrent melanoma growth observed with MEK or BRAF/MEK inhibitor treatment alone.

Conclusions: The combination of MAPK pathway inhibitors with an antibody-drug conjugate targeting GPNMB is an effective therapeutic option for patients with melanoma. Clin Cancer Res; 22(24); 6088-98. ©2016 AACR.

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-16-1192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168941PMC
December 2016
93 Reads

Publication Analysis

Top Keywords

conjugate targeting
16
antibody-drug conjugate
16
gpnmb expression
12
targeting gpnmb
12
mapk pathway
12
inhibitor treatment
12
pathway inhibitors
12
melanosomal differentiation
12
gpnmb
10
melanoma
10
mek inhibitors
8
braf mek
8
braf and/or
8
and/or mek
8
patients melanoma
8
gpnmb effective
8
cdx-011 antibody-drug
8
inhibitors cdx-011
8
braf-mutant melanoma
8
including gpnmb
8

Similar Publications