Pharmacodynamic Characterization of the Efficacy Signals Due to Selective BRAF Inhibition with PLX4032 in Malignant Melanoma

Abstract

PLX4032 has robust activity in BRAF mutated melanoma. The preclinical use of this molecule identifies criteria for its proper clinical application, describes patterns of and reasons for response/resistance, and affords insight into the role of a BRAF mutation in melanoma.

MAPK Pathway Inhibition Enhances the Efficacy of an Anti-Endothelin B Receptor Drug Conjugate by Inducing Target Expression in Melanoma

“…However, in some resistant cells, such as the A2058 in our study, inhibition of phosphorylated ERK and upregulation of EDNRB still occurs in response to MAPK pathway inhibition, resulting in a more favorable response to the anti-EDNRB ADC. This is consistent with a previous study in which a number of melanoma cell lines resistant to PLX4032 upregulated the expression of melanocyte-specific markers in response to the drug (24). This same study used gene expression signatures to define a category of melanoma cell lines that maintained high levels of melanocytic antigens, relative to those with low levels.…”

“…Melanoma cells appear to repress cellular markers of the melanocytic lineage via activation of the MAPK pathway (24)(25)(26)(27). To some extent, this might reflect a normal developmental process used by melanocytic precursors for lineage determination.…”

“…PMEL17 and EDNRB, are suppressed by MAPK signaling (24)(25)(26)(27). As the expression level of a cell surface target can affect the efficacy of an ADC, we evaluated the suitability of combining the anti-EDNRB ADC with the BRAF inhibitors PLX4032 (28) and G590945 and 2 chemically distinct MEK inhibitors GDC-0973 and GDC-0623.…”

The Role of Cellular Differentiation and Cell Fate in Malignant Melanoma

“…These signatures correlate to two distinct populations of melanoma cells, one with a predominantly proliferative phenotype and the other with a predominantly invasive phenotype. Subsequent transcriptional profiling studies in melanoma cells have revealed two discrete states of differentiation (Hoek, 2007;Tap et al, 2010). The first state results in a phenotype closely resembling primary human melanocytes, while the second results in a phenotype resembling neuronal stem cells (Hoek, 2007;Tap et al, 2010).…”

“…Subsequent transcriptional profiling studies in melanoma cells have revealed two discrete states of differentiation (Hoek, 2007;Tap et al, 2010). The first state results in a phenotype closely resembling primary human melanocytes, while the second results in a phenotype resembling neuronal stem cells (Hoek, 2007;Tap et al, 2010). Further, melanoma cells with a proliferative phenotype tend to be in a melanocytic differentiation state, while cells which acquire an invasive phenotype tend to dedifferentiate into a neuronal state.…”