The 5-year survival of metastatic melanoma patients is ~15% and the 5-year survival for stage II (localized) melanoma is only 50-80%. This appears to be due in part to the absence of targeted therapies for BRAF WT (wild-type) metastatic melanomas, which make up ~50% of all metastatic melanomas. This appears to be due in part to an absence of biomarkers and targets for the identification and treatment of aggressive subtypes of stage II BRAF WT melanomas. There is an urgent need to identify biomarkers and targets for aggressive BRAF WT melanomas in order to inform targeted chemotherapy for these patients and to improve outcomes of both metastatic and stage II disease. Our analyses of The Cancer Genome Atlas – Skin Cutaneous Melanoma (TCGA-SKCM) dataset suggest that the ERBB4 receptor tyrosine kinase gene is mutated in 15% of melanomas, with a preference for BRAF WT melanomas. Furthermore, our analyses suggest that the ERBB4 mutations found in the SKCM dataset are not random, but are instead the result of selection. ERBB4 functions as a context-dependent oncogene or tumor suppressor gene and thus ERBB4 mutations may DRIVE malignancies by either conferring a gain of function (GOF) in the contexts in which ERBB4 functions as an oncogene or by conferring a loss of function (LOF) in the contexts in which ERBB4 functions as a tumor suppressor gene. Our analysis also suggests that ERBB4 functions by both cooperating with the RAS pathway and stimulating the PI3K pathway. Thus, we hypothesize that ERBB4 driver mutations exist in a significant fraction of melanomas and that the combination of ERBB4/PI3K and RAS signaling may be a target for therapeutic intervention in ERBB4 mutant/BRAF WT melanomas.
Articulate the need to identify biomarkers indicative of the aggressive subtype(s) of stage II BRAF WT melanoma and new therapeutic targets for BRAF WT melanomas.
Analyze the complexities of ERBB family receptor tyrosine kinase dimerization and signaling in melanoma.
Identify evidence to suggest that ERBB4 mutations in melanoma are non-random and are the result of selection.
Demonstrate how BOTH gain-of-function and loss-of-function ERBB4 mutations may stimulate the PI3K pathway in melanoma and describe the context-dependent manner in which that stimulation may occur.