Abstract A21: Identification of putative melanoma driver mutations in the ErbB4 receptor tyrosine kinase gene

Introduction: Despite the advances in targeted therapies and immunotherapeutics, the 5-year survival rate of metastatic melanoma patients remains about 20%. In part, the high mortality rate is due to the fact that there are currently 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 gene that encodes the ErbB4 receptor tyrosine kinase. This mutation incidence is significantly higher than that of the other ERBB genes in the same data set. However, unlike the validated V600E/K/D/R mutations in the BRAF oncogene, ERBB4 mutations in melanoma are extremely heterogenous with 76 unique ERBB4 nonsynonymous missense mutations, none of which have incidence rates of greater than 1%. 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 ERBB4 mutations contribute to melanoma tumorigenesis. Experimental Procedures/Summary of Data: Consequently, we have used various in silico approaches to predict the functional role of ERBB4 nonsynonymous missense 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 mutation 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. 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 L. Cullum, Taraswi M. Ghosh, Lauren M. Lucas, Damien Waits, Kenneth M. Halanych, David J. Riese. Identification of putative melanoma driver mutations in the ErbB4 receptor tyrosine kinase gene [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr A21.