Pan-erbB inhibition potentiates BRAF inhibitors for melanoma treatment

Abstract

The BRAF inhibitor vemurafenib is currently used for treating patients with BRAF V600E mutant melanoma. However, the responses to vemurafenib are generally partial and of relatively short duration. Recent evidence suggests that activation of the epidermal growth factor receptor (EGFR)/erbB signaling pathway may be responsible for the development of BRAF inhibitor resistance in melanoma patients. In this study, we characterized the erbB family of receptors and ligands in melanoma cell lines and examined whether targeting both BRAF and erbB provided enhanced antitumor activity in BRAF mutant melanoma. Variable levels of erbB2, erbB3, and truncated erbB4 were expressed in both BRAF wildtype and mutant melanoma cells with no significant differences between wildtype and mutant lines. EGFR was rarely expressed. Neuregulin 3 and neuregulin 4 were the major erbB ligands released by melanoma cells. Multi-erbB targeting with the irreversible tyrosine kinase inhibitor canertinib exerted a more effective growth inhibitory effect in both BRAF wildtype and mutant melanoma cells compared with the single-erbB or dual-erbB targeting inhibitors, gefitinib, erlotinib, and lapatinib. Canertinib inhibited both EGF-induced and neuregulin 1-induced erbB downstream signaling in both mutant and wildtype cell lines. However, canertinib induced apoptosis and sub-G1 arrest only in mutant cells. Canertinib statistically increased the antiproliferative effects of vemurafenib in the BRAF mutant melanoma cell lines while little or no enhanced effect was observed with the combination treatment in the wildtype cell lines. A combined inhibition strategy targeting BRAF together with multiple erbB family kinases is potentially beneficial for treating BRAF V600E mutant melanoma. Wildtype BRAF melanoma may also benefit from a multi-erbB kinase inhibitor.

Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

“…This was an immediate effect, which was presumably due to a high plasticity of melanoma cells, and not as a result of depletion of EGFR high subpopulation as reported in BRAF inhibitor-resistant cells [103]. EGFR is expressed in epithelial cells and its overexpression is found in cancers of epithelial origin [110], whereas melanoma cells rarely express EGFR [111]. Positive staining of EGFR was observed only in 13 out of 114 melanoma samples (11.4%), and the staining intensity was predominantly weak to moderate [112].…”

Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment

“…Girotti et al observed a significant reduction in the proliferation of melanoma cells in vitro and in vivo using gefitinib (EGFR and ERBB2 inhibitor) and PLX4720 (BRAF V600E inhibitor), as well as employing dasatinib (tyrosine kinase inhibitor with broad specificity) monotherapy [25]. Administration of a pan-ErbB inhibitor, canertinib, paired with vemurafenib also effectively decreased the growth of melanoma cells [48]. BRAF V600E mutation and drug resistance to BRAF inhibitors occurs also in colorectal cancer.…”

Gefitinib or lapatinib with foretinib synergistically induce a cytotoxic effect in melanoma cell lines

“…Schicher et al found that, in melanoma cell lines and mouse xenografts, erlotinib (an EGFR inhibitor) and bevacizumab (an anti-VEGF monoclonal antibody) act synergistically to decrease proliferation, 3D invasion, and activation of signaling pathways in their cell and animal models [ 38 ]. Other studies have reported the successful application of MET inhibitors paired with an anti-Braf V600E drug [ 39 ] and therapy including the pan-ErbB inhibitor, canertinib, and Braf V600E inhibitor [ 40 ]. In another study, Liu et al successfully applied foretinib in combination with lapatinib against various cancer cell lines but no melanoma cells were tested [ 22 ].…”