Abstract 4371: ERBB4 heterodimers appear to drive BRAFWT melanoma cell lines

Abstract

Abstract Purpose of The Study: To determine whether heterodimerization of ERBB4 with EGFR or ERBB2 drives the proliferation of BRAF WT melanoma cell lines. Introduction: Metastatic melanomas that possess wild-type (WT) BRAF alleles are just as aggressive as melanomas that harbor gain-of-function (e.g., V600E) BRAF alleles. Moreover, no targets for effective chemotherapeutic intervention (other than immune checkpoint inhibitors) have been identified for these tumors. Thus, our goal is to identify candidate targets for therapeutic intervention in BRAF WT melanomas. ERBB4 (HER4) is a receptor tyrosine kinase that is closely related to the epidermal growth factor receptor (EGFR/ERBB1/HER1), ERBB2 (Neu/HER2), and ERBB3 (HER3). 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 inhibits the proliferation of BRAF WT melanoma cell lines. We have also previously demonstrated that ERBB4-EGFR and ERBB4-ERBB2 heterodimers stimulate proliferation and other oncogenic phenotypes in a variety of tumor model systems. Hence, here we test the hypothesis that ERBB4-EGFR or ERBB4-ERBB2 heterodimers drive BRAF WT melanomas. Experimental Approach: We are testing whether wild-type EGFR or ERBB2 alleles stimulate the proliferation of four different human BRAF WT melanoma cell lines. We are testing whether the dominant-negative EGFR (K721A) or ERBB2 (K753A) mutant alleles inhibit the proliferation of these cell lines. Likewise, we are testing whether EGFR or ERBB2 shRNAs inhibit the proliferation of these cell lines. Finally, we are testing whether EGFR or ERBB2 enables ERBB4 mutant alleles found in BRAF WT melanoma samples to drive greater levels of proliferation in 32D cells than wild-type ERBB4. Unpublished Results: Wild-type ERBB2 causes a significant increase in the proliferation of the MEL-JUSO and IPC-298 BRAF WT female melanoma cell lines. The ERBB2 dominant-negative allele causes a significant decrease in the proliferation of these cell lines. Finally, preliminary data suggest that the EGFR and ERBB2 dominant-negative alleles inhibit the proliferation of the MeWo BRAF WT male melanoma cell line. Preliminary Conclusions: Our data suggest that ERBB2-ERBB4 heterodimers drive two female BRAF WT melanoma cell lines, whereas ERBB2-ERBB4 and EGFR-ERBB4 heterodimers drive a male BRAF WT melanoma cell line. Thus, we predict that FDA-approved ERBB2 inhibitors (and in some cases, EGFR inhibitors) may be effective in ERBB4-dependent, BRAF WT melanomas. Moreover, ERBB4 heterodimerization with ERBB2 or EGFR may account for the gender disparities observed in BRAF WT melanomas. Citation Format: Vipasha Dwivedi, Lauren M. Lucas, Jen Davis, Kaitlyn O'Daniel, Rees H. Cooke, Joelle N. Woggerman, Ella N. Wilson, Maddy N. Ingrao, David J. Riese. ERBB4 heterodimers appear to drive BRAFWT melanoma cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4371.