Abstract 5869: Investigation of molecular alterations associated with double resistance to BRAF and MEK inhibition in melanoma

Abstract More than 50% of melanomas harbor activating BRAF kinase mutations, with BRAFV600E representing more than 90% of BRAF mutations. Inhibition of mutant BRAF by BRAF inhibitors (BRAFi) in patients with advanced melanoma yields a remarkable initial clinical response. Limited duration response and disease recurrence of inhibitors occurs due to acquired drug resistance. Recently identified mechanisms of MAPK hyperactivation in acquired resistance to BRAFi have encouraged clinicians to employ a combination of BRAF and MAPK inhibitors to block the MAPK signaling pathway more effectively. However, most patients treated with this combination therapy still relapse due to de novo drug resistance. Therefore, innovative strategies are still necessary to improve the precision and durability of anti-melanoma therapies. To investigate the mechanism of both BRAFi and MEKi resistance (double resistance, DR) in mutant BRAF melanomas, we have developed models from four human melanoma cell lines to explore the hypothesis that molecular alterations are related to double resistance to BRAFi and MEKi in melanoma. We have found that BRAFi-MEKi double-resistant models exhibit distinct differences in morphology and growth kinetics. Specifically, BRAFi-MEKi double-resistant human melanomas express a higher level of FGFb and PAI-1 expression. We confirmed that overexpression of FGFb and PAI-1 in parental cells could increase the ability to resist BRAF and MEK inhibition. Additionally, we discovered that decreased expression of FGFb and PAI-1, via knock-down, inhibition, or CRISPR in double resistant cells, can restore cell sensitivity to treatments of BRAFi and MEKi. To further elucidate the role of FGFb and PAI-1 on resistant melanoma, we have extended our scope to in vivo mouse xenograft models. Our findings uncovered the mechanism of how melanoma cells can escape BRAFi and MEKi attacks and offer a rational strategy to guide future clinical treatments. Citation Format: Armond J. Isaak, GeGe R. Clements, Lei Huang, Yifei Qin, Qiang Zho, Glenn Merlino, Yanlin Yu. Investigation of molecular alterations associated with double resistance to BRAF and MEK inhibition in melanoma abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5869.