Abstract 2144: Mutations in ERBB4 may account for clinical resistance of melanomas to inhibitors of the RAS/RAF/MEK/MAPK pathway

Abstract

Introduction: Despite advancements made in the treatment of metastatic melanoma, the 5-year survival rate remains about 20%. The high mortality rate is thought to be due to there being no other clinically actionable targets other than those that have been identified in the RAS/RAF/MEK/MAPK pathway. Our analyses of The Cancer Genome Atlas (TCGA) Skin Cutaneous Melanoma (SKCM) data set revealed that 15% of the cases harbor at least one nonsynonymous missense mutation in the ERBB4 gene. This mutation incidence is significantly higher than that of the other ERBB genes in the same data set. Additionally, 91% of cases that harbor a nonsynonymous missense ERBB4 mutation also harbor a known melanoma driver mutation in the RAS/RAF/MEK/MAPK pathway suggesting interplay between ErbB4 signaling and the RAS/RAF/MEK/MAPK pathway. However, unlike the validated BRAF melanoma oncogene, ERBB4 mutations in melanoma are extremely heterogenous with 76 unique ERBB4 nonsynonymous missense mutations. None of which have incidence rates of greater than 2%. Furthermore, some of these ERBB4 mutations have already been shown to be necessary for the proliferation of some human melanoma cell lines, demonstrating a need to determine which ERBB4mutations contribute to melanoma tumorigenesis and clinical resistance. Experimental Procedures/Summary of Data: Consequently, various in silico approaches were used to prioritize ERBB4 mutations in melanoma. We found that many TCGA-SKCM ERBB4 mutations affect highly conserved regions. Indeed, 57 ERBB4 mutations affect a residue that is conserved in at least one other ErbB receptor. Moreover, 7 ERBB4 mutations affect a residue that is conserved in another ErbB receptor and is the location of a gain-of-function mutations in the other ERBB gene. Fifteen (15) of the putative ERBB4 melanoma driver mutations are found in other tumor types, and 3 transform the growth of fibroblasts and exhibit ligand-independent signaling. And, finally, we found that the combination of the ERBB4 E542K and E872K mutations and the E452K mutation alone are necessary for the proliferation of some human melanoma cell lines. Conclusions: Unlike genes such as BRAF or NRAS, which contain a single or a small number of “hot spot(s)” for driver mutations, the ERBB4 gene appears to harbor numerous mutations that are likely to function as drivers of melanoma tumorigenesis. Whereas some of the ERBB4 mutations found in melanoma have been identified as bona fide melanoma drivers, most remain uncharacterized. The results of these analyses indicate that many of these uncharacterized mutations are likely to contribute to the malignant phenotype of melanoma. Therefore, there remains a need to distinguish which ERBB4 mutations function as drivers and can serve as biomarkers for response to therapies that disrupt ErbB4 signaling. Citation Format: Richard Lee Cullum, Taraswi Ghosh, Lauren Lucas, Damien Waits, David Riese. Mutations in ERBB4 may account for clinical resistance of melanomas to inhibitors of the RAS/RAF/MEK/MAPK pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2144.