Abstract B072: Is targeting ERBB2-ERBB4 heterodimers with monoclonal antibodies effective against wild-type BRAF melanomas?

Abstract Introduction: No effective targeted therapies exist for wild-type BRAF (BRAF-WT) melanomas. Likewise, immune checkpoint inhibitors are less effective against BRAF-WT melanomas than melanomas that carry driver mutations in BRAF. Thus, our goal is to improve the prognosis of BRAF-WT melanoma patients by developing effective targeted therapies against these tumors. Methods and Results: We have previously observed that three BRAF-WT melanoma cell lines exhibit ERBB4- and ERBB2-dependent proliferation. Thus, we postulate that ERBB4-ERBB2 heterodimers drive these cell lines. We are testing this hypothesis using the mouse monoclonal antibody (mAb) 2C4 (the antecedent of the FDA-approved drug pertuzumab), which binds ERBB2 and disrupts signaling by ERBB2 heterodimers. As controls, we are using the mAbs 4D5 (the antecedent of the FDA-approved drug trastuzumab), which binds ERBB2 and disrupts signaling by ERBB2 homodimers; 225 (the antecedent of the FDA-approved drug cetuximab), which binds EGFR and disrupts its signaling; 528, which binds EGFR but does not effectively inhibit EGFR signaling; and 4G10, an antiphosphotyrosine mAb that does not inhibit cellular proliferation. We have cultured the five hybridomas and purified the mAbs from the conditioned media. Yields range from 5-15 mg, and the purity exceeds 95%. We are currently testing the effects of the mAbs against the three ERBB4- and ERBB2-dependent BRAF-WT melanoma cell lines. BRAF-WT melanomas typically possess mutations in RAS or NF1 genes that stimulate RAS/MAPK signaling. Thus, in ERBB4- and ERBB2-dependent BRAF-WT melanomas, we postulate that ERBB4-ERBB2 heterodimers stimulate signaling by the PI3 kinase pathway, which cooperates with elevated RAS/MAPK signaling to drive proliferation. Consequently, should 2C4 or 4D5 specifically inhibit the proliferation of the BRAF-WT melanoma cell lines, we will test whether a combination of an effective mAb with cobimetinib (an FDA-approved MEK inhibitor) has greater antiproliferative activity than either drug by itself. Anticipated Conclusion: This work uses agents that could be readily translated into clinical settings. Thus, the anticipated results could spur the translation of ERBB and MEK inhibitors into clinical trials and may lead to sorely needed advancements in treating BRAF-WT melanomas. Citation Format: Victoria E. Huffman, David J. Riese II, Charleigh Gumapac, Nick DeFeo, Mary Tate Reese, Allie Pegel, Markelle Scott, Teigan Nelson, Ella Wilson, Haram Kim, Angelina Shunnarah. Is targeting ERBB2-ERBB4 heterodimers with monoclonal antibodies effective against 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 B072.