Biology subjects

Riese, D. J.

Publications and source records attributed to Riese, D. J..

2 recordsLinked to original sources

bioRxiv2026

Cancer Cell Line Encyclopedia Data Suggest that Ligands for ERBB Family Receptors May Drive BRAF-WT Melanomas

I.Cutaneous skin melanomas with wild-type BRAF alleles ("BRAF-WT melanomas") remain relatively difficult to treat, even though they typically possess driver mutations in a RAS gene or NF1. For example, these tumors respond relatively poorly to combinations of MEK and BRAF inhibitors, and their response to ICIs is muted compared to the response of BRAF-mutant melanomas. ERBB2 and ERBB4, which encode receptor tyrosine kinase genes, are necessary and sufficient for the proliferation of multiple BRAF-WT melanoma cell lines. Consequently, we have postulated that ERBB4-ERBB2 heterodimerization drives BRAF-WT melanomas. This mechanism is consistent with the observation that elevated ERBB4 transcription or ERBB4 mutations are found in a significant fraction of BRAF-WT melanoma tumor samples. Moreover, a subset of ERBB4 mutations found in BRAF-WT melanoma samples increases proliferation in a BRAF-WT melanoma cell line. Because the elevated ERBB4 transcription observed in BRAF- WT melanomas is typically insufficient to cause ligand-independent ERBB4 signaling, we have postulated that ligands for ERBB family receptors drive the elevated ERBB4-ERBB2 heterodimerization responsible for the proliferation of BRAF-WT melanoma cell lines. We have explored this hypothesis by analyzing data found in the Broad Institutes Cancer Cell Line Encyclopedia. These data suggest that some EGF family hormones are required for the proliferation of BRAF-WT melanoma cell lines. Likewise, the G11/Gq pathway, which can stimulate cleavage and maturation of EGF family hormones, is also required for the proliferation of BRAF-WT melanoma cell lines. Thus, these data suggest additional therapeutic targets in BRAF-WT melanomas. Moreover, because many uveal (ocular) melanomas possess elevated G11/Gq signaling, these data suggest that ligand stimulation of ERBB receptor signaling may contribute to uveal melanomagenesis or progression.

cancer biology↗

bioRxiv2024

Human melanoma cell lines that possess wild-type BRAF alleles but are dependent on ERBB4 and ERBB2

Metastatic skin cutaneous melanomas that contain wild-type BRAF alleles typically possess an activating mutation in a RAS allele or a loss-of-function mutation in an NF1 allele ("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 of BRAF mutant melanomas to these agents, and additional validated targets for therapeutic intervention have yet to be identified. Previous work from our laboratory has demonstrated that ERBB4 is 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 Q646C ERBB4 mutant 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) ERBB2 K753A mutant allele inhibits the clonogenic proliferation of the IPC-298, MEL-JUSO, and MeWo ERBB4-dependent, BRAF-WT&RAS/NF1-mutant melanoma cell lines. Moreover, the kinase-deficient (dominant-negative) EGFR K721A 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-2 ERBB4-dependent, BRAF-WT&RAS/NF1-mutant melanoma cell line is unaffected by the ERBB2 K753A or EGFR K721A 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.

cancer biology↗