Role Of Igf1r In Mediating Resistance To Mapk Pathway Inhibitors In Braf-Mutant Melanoma

Melanoma is the most aggressive form of skin cancer originating in the pigment producing melanocytes of the skin. The five year survival rate for patients diagnosed with metastatic melanoma is only 23%. Around 60% of the melanomas encompass the active BRAFV600E oncoprotein, which is critical for survival and proliferation of the melanoma cells as a consequence of hyperactivation of theMAPK pathway. This opened up avenues for development of BRAF inhibitors and subsequently the development of MEK inhibitors. Co-targeting of BRAF and MEK with Dabrafenib and Trametinib respectively, results in a response rate of about 70% in patients harboring the BRAF mutation. The use of these inhibitors is limited as patients relapse on treatment typically within 6 months due to the development of acquired resistance. Recent studies have identified various resistance mechanisms including involvement of various receptor tyrosine kinases. In order to decipher novel mechanisms of resistance, we generated double resistant cell lines to BRAF and MEK inhibitor in WM115, WM983 and A375 human melanoma cell lines harboring BRAFV600 mutations using Dabrafenib and Trametinib over a course of 9-11 months. The drug resistant cell lines exhibited increased viability and maintenance of downstream p-ERK protein as compared to their drug sensitive counterparts. Receptor tyrosine kinase array revealed an increase in phosphorylated HER3, AXL, EGFR and IGF1R in the drug resistant cells versus drug sensitive cells. Quantitative PCR data revealed an upregulation of these molecules along with an increase in the expression of some of their ligands at the mRNA level. RNA-seq analysis identified IGF1R and IGF2BP2 to be upregulatedin the resistant cell lines compared to parental cell lines.IGF2BP2 is a tumor promoter and drives cancer proliferation in a variety of malignancies and is correlated with poor survival.Our next experiments are focused on testing the efficacy of IGF1R inhibitors in the drug resistant cell lines and their downstream effector signaling molecules in vitro and in vivo. Further, we aim to decipher the mechanism by which IGF2BP2 regulates the IGF1R signaling pathway in MAPK inhibitors resistant melanoma setting. Delineating the role of IGF1R in mediating resistance to BRAF and MEK inhibitors will help expand possible treatment options to aid in long-term success for BRAF-mutant melanoma patients. Citation Format: Hima Patel, Rosalin Mishra, Natasa Broit, Nour Yacoub, Long Yuan, Samar Alanazi, Nicholas Hayward, Peter Johansson, Joan T. Garrett. Role of IGF1R in mediating resistance to MAPK pathway inhibitors in BRAF-mutant melanoma [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 1894.