Abstract B065: Using Mutations in a Dimerization Interface of ERBB4 and ERBB2 to Elucidate the Role of ERBB4-ERBB2 Heterodimers in wild-type BRAF Melanomas

Abstract Introduction: Melanoma is an aggressive and deadly subtype of skin cancer. Approximately half of melanomas harbor a gain-of-function mutation in a BRAF allele. The growth of these tumors is reduced by immune checkpoint inhibitors (ICIs) or a combination of BRAF and MEK inhibitors. Unfortunately, the melanomas that possess a wild-type BRAF allele (BRAF-WT melanomas) are not responsive to targeted therapeutics, and ICIs are not highly effective against these tumors. Thus, our long-term goal is the development of drugs that are effective against BRAF-WT melanomas. Methods and Anticipated Results: We have previously shown that expression of the ERBB4 receptor tyrosine kinase gene is both sufficient and necessary to drive the proliferation of four BRAF-WT melanoma cell lines. ERBB4 encodes a receptor tyrosine kinase that is closely related to the Epidermal Growth Factor Receptor (EGFR), ERBB2 (HER2), or ERBB3 (HER3). Moreover, three ERBB4-dependent, BRAF WT melanoma cell lines also depend on ERBB2. Previous data indicate that ERBB4 homodimers inhibit tumor cell proliferation. Thus, we hypothesize that ERBB4-ERBB2 heterodimers drive these ERBB4- and ERBB2-dependent, BRAF-WT melanoma cell lines. To test this hypothesis, we are evaluating the activity of mutant alleles that affect the cytoplasmic ERBB2/ERBB4 asymmetric dimer interface. We are testing whether mutations in the N-lobe of the ERBB4 kinase domain cause loss-of-function phenotypes (reduced signaling and stimulation of proliferation) and whether mutations in the C-lobe of the ERBB2 kinase domain cause loss-of-function phenotypes. Finally, we will test whether the activity of loss-of-function ERBB4 N-lobe mutant alleles can be rescued by loss-of-function ERBB2 C-lobe mutant alleles. Anticipated Conclusion: Positive results would suggest that ERBB4-ERBB2 heterodimers drive the proliferation of ERBB4- and ERBB2-dependent melanomas and that such melanomas will respond to combination therapies that feature FDA-approved anti-ERBB2 agents, including pertuzumab and lapatinib. Citation Format: Teigen Nelson, Markelle T. Scott, Ella Wilson, Victoria Huffman, Nick DeFeo, Haram Kim, David Riese. Using Mutations in a Dimerization Interface of ERBB4 and ERBB2 to Elucidate the Role of ERBB4-ERBB2 Heterodimers in wild-type BRAF Melanomas [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B065.