Abstract 5932: Targeting BRAF WT metastatic melanomas: Identifying ERBB4 mutations as biomarkers for novel combinatorial treatment strategies
Authors: Lucas Lauren , Cullum Richard , Waits Damien , Ghosh Taraswi , Cook Laura , Kaufmann David , Markham Jessica , Rael Cristina , Halanych Kenneth , David Allan , Riese David 
Published: September 2020

Abstract
Introduction: The treatment of metastatic melanoma (MM) has been dramatically improved through the use of BRAF and MEK inhibitors in patients whose tumors harbor activating mutations in BRAF. However, these mutations occur in only ~50% of MMs and a targeted therapy(ies) has yet to be identified for those MMs that contain wild-type (WT) BRAF. Using The Cancer Genome Atlas metastatic melanoma (TCGA-SKCM) dataset, we have discovered that 50% of BRAF WT melanomas harbor a missense mutation in ERBB4, which encodes a member of the epidermal growth factor receptor (EGFR/ErbB1) family of receptor tyrosine kinases. Hence, our goal is to evaluate whether ERBB4 mutant alleles function as biomarkers and targets for therapeutic intervention in BRAF WT MMs.
Experimental Procedures/Data Summary: Of the 469 genomes in the TCGA-SKCM dataset, 70 harbor at least one missense mutation in ERBB4, resulting in a total of 76 unique ERBB4 missense mutations. These mutations do not appear to be random occurrences, but instead appear to be the result of selection. For example, the incidence of ERBB4 mutant alleles is greatly reduced in melanomas that possess BRAF driver mutations and/or driver events in PI3K pathway genes. In contrast, the incidence of ERBB4 mutant alleles is markedly elevated in melanomas that possess genetic alterations that result in elevated RAS signaling. Indeed, melanomas that possess an ERBB4 mutant allele AND a genetic alteration that results in elevated RAS signaling are associated with a marked decrease in survival. Taken together, these data indicate that ERBB4 mutant alleles cause elevated PI3K signaling, which cooperates with elevated RAS signaling to drive the genesis and/or progression of BRAF WT MMs.
The existence of 76 unique ERBB4 mutations in the TCGA-SKCM dataset highlights one of the challenges in identifying the ERBB4 mutant alleles that function as bona fide BRAF WT MM drivers. The other challenge is that ERBB4 functions as a context-dependent oncogene and tumor suppressor gene. Hence, we will describe the ongoing development and validation of innovative, positive-selection screens for gain-of-function ERBB4 mutant alleles and for loss-of-function ERBB4 mutant alleles from the library of ERBB4 mutant alleles found in the TCGA-SKCM dataset. The gain-of-function ERBB4 mutant alleles would enhance ERBB4 signaling in contexts in which ERBB4 functions as an MM oncogene, whereas the loss-of-function ERBB4 mutant alleles would disrupt ERBB4 signaling in contexts in which ERBB4 functions as an MM tumor suppressor gene.
Conclusions: In silico analyses of the TCGA-SKCM dataset indicate that ERBB4 mutant alleles function as drivers of BRAF WT MM. We will present our progress in developing and validating positive selection strategies to identify which of the 76 ERBB4 mutant alleles found in the TCGA-SKCM dataset function as bona fide drivers of BRAF WT MMs.
Citation Format: Lauren Lucas, Richard Cullum, Damien Waits, Taraswi Ghosh, Laura Cook, David Kaufmann, Jessica Markham, Cristina Rael, Kenneth Halanych, Allan David, David Riese. Targeting BRAF WT metastatic melanomas: Identifying ERBB4 mutations as biomarkers for novel combinatorial treatment strategies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5932.