Abstract 98: The role of HORMAD1 in transformation of keratinocytes following vemurafenib treatment

Abstract

Abstract BRAF inhibitor (BRAFi) therapies are highly effective treatments for metastatic melanoma. However, BRAFi monotherapies are associated with a significant risk of squamous cell carcinoma (SCC) development in melanoma patients. Consequently, BRAF inhibition results in an unanticipated activation of the MAPK pathway in surrounding cells that harbour wildtype BRAF. Fortunately, a combination approach with both a BRAFi and the selective MAPK inhibitor (MEKi), trametinib, attenuates BRAFi-induced risk of SCCs. Despite the fact that this combination therapy is widely used in clinical practice, the mechanisms associated with SCC induction and why this effect is attenuated with a MEK inhibitor remain poorly understood. HORMAD1, a meiosis specific gene, has been shown to have an impact on genomic instability and proliferation in the development of SCCs. Moreover, recent work in our lab has demonstrated that the MAPK pathway regulates HORMAD1 expression in SCC cell lines. Therefore, we sought to investigate a potential role of HORMAD1 in the risk and development of SCCs as a mechanism of BRAFi that is attenuated with the co-administration of the MEKi, trametinib. Using the BRAFi, vemurafenib, we inhibited the kinase activity of activated BRAF (V600E) and the MEKi, trametinib to evaluate the expression of HORMAD1 in melanoma and normal keratinocyte cell lines. To determine the effects of these two inhibitors, a cell proliferation assay was conducted followed by the evaluation of various components of cell cycle regulation and genomic instability. We found that HORMAD1 protein expression levels increased following treatment with the BRAFi, vemurafenib, in the normal keratinocyte cell line, HaCaT, but not in the melanoma cell line, A375. In contrast, HORMAD1 expression decreased following treatment with the MEKi, trametinib in both HaCaT and A375. Cell proliferation assays depict a vulnerability to both vemurafenib and trametinib in both normal and melanoma cell lines, however, HaCaT cells appear to be more susceptible to increased levels of genomic instability following treatment with vemurafenib when compared to A375. Our results suggest that HORMAD1 likely plays a key role in the development of SCCs by increasing genomic instability and proliferation in normal keratinocytes following BRAFi monotreatment. The increased risk of SCC formation is attenuated by dampening HORMAD1 levels with the co-administration of the MEKi, trametinib. Citation Format: Jennifer Gantchev, Amelia Martinez Villarreal, Brandon Ramchatesingh, Ivan V. Litvinov. The role of HORMAD1 in transformation of keratinocytes following vemurafenib treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 98.