Abstract 1887: Tumor-stroma interactions mediated by Semaphorin 6A as a determinant of drug resistance in BRAF-mut melanoma

Abstract

Abstract In BRAF-mutant (BRAF-mut) melanoma combined BRAF/MEK inhibition increases survival. However, pharmacological effects on the genetically “normal” tumor microenvironment (i.e. paradox MAPK activation) may set the stage for the development of drug resistance. In melanoma specimens, we observed a significant correlation between BRAF-mut and the expression of Semaphorin 6A (Sema6A), a member of the semaphorin family that regulates actin cytoskeleton remodeling, motility and cell proliferation. In BRAF-mut melanoma cell lines, Sema6A is involved in cytoskeleton remodeling by regulation of YAP activity. Sema6A depletion induced a decrease in RhoA activation and, consequently, an increase in phospho-YAP and a reduction in cell proliferation rate. We thus hypothesized that actin cytoskeleton remodeling and dynamic evolutions may play a role in both cell autonomous and stroma-mediated mechanisms of drug-resistance in this context. To assess the functional relevance of Sema6A expression in the regulation of melanoma/stroma interactions and sensitivity/resistance to pathway inhibitors, we performed an inducible Sema6A knock down in BRAF-mut melanoma cell lines and evaluated the response to BRAF/MEK inhibitors in monolayer and 2D co-culture systems. In contexts of partial response or resistance in vitro, BRAF inhibitors, alone or combined with MEK inhibitors, were increased Sema6A expression at the mRNA and protein levels in both monolayer and 2D co-culture systems. Furthermore, Sema6A silencing performed in 2D co-culture system abrogated the protective effect of melanoma/stroma interactions, resulting in a synergistic effect with BRAF/MEK inhibitors. Overall, our results suggest that Sema6A could be a crucial mediator of protective tumor/stroma interactions, involved in resistance to MAPK inhibition in melanoma. Citation Format: Rossella Loria, Italia Falcone, Marta Di Martile, Valentina Caprara, Rocco Fraioli, Valentina Laquintana, Giulia Bon, Laura Rosanò, Donatella Del Bufalo, Ludovica Ciuffreda, Virginia Ferraresi, Michele Milella, Rita Falcioni. Tumor-stroma interactions mediated by Semaphorin 6A as a determinant of drug resistance in BRAF-mut 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 1887.