Human melanoma cell lines that possess wild-typeBRAFalleles but are dependent onERBB4andERBB2

Abstract

Metastatic skin cutaneous melanomas that contain wild-typeBRAFalleles typically possess an activating mutation in aRASallele or a loss-of-function mutation in anNF1allele ("BRAF-WT&RAS/NF1-mutant melanomas"). Nonetheless, these tumors remain a significant clinical challenge; they are resistant to MEK and BRAF inhibitors, their response to immune checkpoint inhibitors is less robust than the response ofBRAFmutant melanomas to these agents, and additional validated targets for therapeutic intervention have yet to be identified. Previous work from our laboratory has demonstrated thatERBB4is required for the proliferation of the IPC-298, MEL-JUSO, MeWo, and SK-MEL-2 BRAF-WT&RAS/NF1-mutant melanoma cell lines. Surprisingly, the synthetic constitutively dimerized and active Q646CERBB4mutant allele appears to strongly inhibits the proliferation of BRAF-WT&RAS/NF1- mutant melanoma cell lines. Given that we have also previously demonstrated that ERBB4- ERBB2 and ERBB4-EGFR heterodimers are more potent drivers of proliferation than are ERBB4 homodimers, here we begin to test the hypothesis that ERBB4 heterodimers drive the proliferation of BRAF-WT&RAS/NF1-mutant melanoma cell lines. Here we demonstrate that the kinase-deficient (dominant-negative)ERBB2K753A mutant allele inhibits the clonogenic proliferation of the IPC-298, MEL-JUSO, and MeWoERBB4- dependent, BRAF-WT&RAS/NF1-mutant melanoma cell lines. Moreover, the kinase-deficient (dominant-negative)EGFRK721A mutant allele inhibits the clonogenic proliferation of the MeWo cell line, but not the IPC-298 or MEL-JUSO cell lines. Finally, the clonogenic proliferation of the SK-MEL-2ERBB4-dependent, BRAF-WT&RAS/NF1-mutant melanoma cell line is unaffected by theERBB2K753A orEGFRK721A dominant-negative mutant alleles. We discuss these findings in the context of our hypothesis that ERBB4 heterodimers drive the proliferation of BRAF-WT&RAS/NF1-mutant melanoma cell lines.