Abstract B059: ERBB4 heterodimers drive wild-type <i>BRAF</i> melanoma cell lines

Abstract Introduction: Metastatic melanomas that possess wild-type (WT) BRAF alleles (“BRAF-WT melanomas”) are less responsive to targeted therapies and immune checkpoint inhibitors than BRAF-WT melanomas. Thus, we aim to identify targets for therapeutic intervention in these tumors. Methods: ERBB4 (HER4) encodes a receptor tyrosine kinase closely related to the epidermal growth factor receptor (EGFR), ERBB2, and ERBB3. We have previously demonstrated that ERBB4 is both sufficient and necessary for the proliferation of BRAF-WT melanoma cell lines. However, the constitutively homodimerized ERBB4 Q646C mutant protein inhibits the proliferation of BRAF-WT melanoma cell lines. Moreover, we have demonstrated that ERBB4-EGFR and ERBB4-ERBB2 heterodimers stimulate proliferation and other oncogenic phenotypes in various tumor model systems, in many cases through stimulation of the PI3 kinase (PI3K) pathway. Hence, in this work, we have used a dominant-negative ERBB2 allele to test the hypothesis that ERBB4-ERBB2 heterodimers drive BRAF-WT melanomas. Results: Blocking ERBB2 signaling using a dominant-negative ERBB2 mutant allele inhibits proliferation by three ERBB4-dependent BRAF-WT melanoma cell lines, indicating that ERBB4-dependent BRAF-WT melanoma cell lines are also ERBB2 dependent. We are testing whether changes in ERBB2 tyrosine phosphorylation accompany changes in ERBB4-dependent proliferation. Moreover, in the three ERBB4- and ERBB2-dependent BRAF-WT melanoma cell lines, we are evaluating the potency of the FDA-approved irreversible EGFR/ERBB2/ERBB4 inhibitor afatinib. We are testing afatinib as a monotherapy and in combination with the MEK inhibitor cobimetinib. BRAF-WT melanomas typically possess mutations in RAS or NF1 genes that stimulate RAS/MAPK signaling. Thus, we predict that combining cobimetinib (which will block MAPK signaling) with afatinib (which will block ERBB/PI3K signaling) will be more effective than either drug by itself. Anticipated Conclusions: Because the translational component of this work utilizes FDA-approved agents, the anticipated results could spur the translation of ERBB and MEK inhibitors into clinical trials and may lead to sorely needed advancements in the treatment of BRAF-WT melanomas. Citation Format: Vipasha Dwivedi, Chloe Dion, Rees Cooke, Emily Allen, Kaitlyn O'Daniel, Douglas Woodall, Lauren Lucas, David John. Riese, Jen Correa. Giraldo. ERBB4 heterodimers drive wild-type BRAF melanoma cell lines [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 B059.