Pharmacologically enhanced expression of the melanoma-associated target, GPNMB, increases the sensitivity of melanoma cells to the CR011-vcMMAE antibody-drug conjugate

A68 GPNMB is a type IA cell-surface glycoprotein expressed by certain types of cancers including malignant melanoma and glioblastoma. We previously generated an antibody to the extracellular domain of GPNMB, conjugated the antibody to the cytotoxic drug monomethylauristatin E (MMAE) via a protease-sensitive linker to facilitate release of drug following internalization, and found that this antibody-drug conjugate (ADC) effectively targeted GPNMB-expressing tumor cells in vitro and in xenograft models. The ADC, designated CR011-vcMMAE, is currently in Phase I clinical testing. Toward the goal of maximizing the anticancer activity of CR011-vcMMAE, we screened for compounds that increased expression of GPNMB on the surface of tumor cells. Our analyses lead to the identification of compounds falling into two main categories. The first of these categories is comprised of inhibitors of the ERK pathway which strongly increased GPNMB expression in melanoma cells harboring activating mutations in NRAS or BRAF, which account for ~80% of all melanomas. The ERK pathway represents a clinically relevant pathway in oncology drug development, and pharmacological inhibitors of this pathway appear to increase GPNMB expression via a transcriptional mechanism. An examination of a variety of melanoma-associated targets other than GPNMB demonstrated that some, but not all of these other proteins, were also induced by inhibitors of the ERK pathway in melanoma cells and that by way of comparison, GPNMB represented one of the most consistently expressed and strongly induced proteins among those surveyed. As would be predicted, melanoma cells exposed to inhibitors of the ERK pathway were sensitized to the growth-inhibitory effects of CR011-vcMMAE. The second category of compounds that increased GPNMB surface expression did so in both melanoma and glioblastoma cells regardless of NRAS/BRAF mutational status, apparently by enhancing the stability and/or membrane localization of GPNMB. The results presented in this study increase our understanding of GPNMB as an oncology target and provide preclinical support for maximizing the activity of CR011-vcMMAE through use in combination with compounds that enhance the cell-surface expression of GPNMB.