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

Abstract

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 TCGA 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 melanoma patients taken before, during and after disease progression on MAPK inhibitor treatment. Sub-cutaneous 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 pre-treatment 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 pre-clinical 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.

A non-coding function of TYRP1 mRNA promotes melanoma growth

“…Three properties support this function. First, TYRP1 is highly expressed in most melanoma 28,29,45,46 . Second, the SNP rs683 genetically determines TYRP1 miRNA sponge activity.…”

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

“…Targeting MITF High /differentiated cells is also possible using a drug-conjugated antibody against GPNMB, a melanosomal antigen ( Fig. 4; Rose et al 2016;Ott et al 2017). Combined with approaches specifically aimed at the MITF Low dedifferentiated or NCSC populations these agents may prove useful in eradicating the MAPK pathway inhibitor-refractory pool of cells and convert targeted antimelanoma therapy into a curative approach.…”

A phase 2 study of glembatumumab vedotin, an antibody‐drug conjugate targeting glycoprotein NMB, in patients with advanced melanoma

“…Preclinical data have demonstrated that gpNMB expression is upregulated in melanoma cell lines after exposure to the MEK inhibitor trametinib, and the combination of glembatumumab vedotin with MEK and BRAF inhibitors (trametinib with or without dabrafenib) enhanced tumor regression in xenograft models . MAPKi therapy in patients with melanoma induced the upregulation of gpNMB transcripts in tumors and increased levels of soluble gpNMB in serum . Although the high expression of gpNMB in melanoma cells observed in the current study may limit this strategy in melanoma, an association of antitumor activity with gpNMB expression was observed in patients with advanced breast cancer who received treatment with glembatumumab vedotin .…”

“…A potential rational strategy for further development of glembatumumab is the combination with mitogen‐activated protein kinase (MAPK) inhibitors (MAPKi) such as BRAF, MEK, and extracellular signal‐regulated kinase (ERK) inhibitors. Preclinical data have demonstrated that gpNMB expression is upregulated in melanoma cell lines after exposure to the MEK inhibitor trametinib, and the combination of glembatumumab vedotin with MEK and BRAF inhibitors (trametinib with or without dabrafenib) enhanced tumor regression in xenograft models . MAPKi therapy in patients with melanoma induced the upregulation of gpNMB transcripts in tumors and increased levels of soluble gpNMB in serum .…”

“…High tumor gpNMB expression is associated with shorter metastasis‐free survival and overall survival (OS) in breast cancer, small cell lung cancer, renal cell cancer, and glioblastoma . gpNMB also is upregulated in melanomas that have BRAF valine mutations at codon 600 (BRAF V600 ) after BRAF/MEK inhibition …”