Abstract PR18: Comparative screening of skin-derived NCSCs, melanocytes, and melanoma developmental programs reveals LPAR1 in MAPKi resistance

Despite the high efficacy of BRAFi/MEKi in BRAF-MT melanomas, resistance arises in the majority of cases. Melanoma hijacks developmental pathways that drive aggressiveness; however, gene signatures shared by melanocyte progenitor cells and melanoma cells remain poorly understood. Here, we define common dependencies in neural crest stem cells (NCSCs) and melanoma cells not present in melanocytes through computational transcriptome analyses and targeted siRNA screens against shared developmental genes. Secondary validation coupled with Ingenuity Pathway Analysis identified the LPAR1-RAPGEF5-RAP1A axis as the top pathway critical for stem cell maintenance and melanoma aggressiveness. Genome-wide gene expression data in the CCLE demonstrates LPAR1 correlates with the MITFlo/AXLhi intrinsic MAPKi resistance signature. In agreement, LPAR1 is elevated in MAPKi-resistant PDX models, and in a subset of post-treatment tumor biopsies from patients who relapsed on MAPKi, relative to respective paired pretreatment biopsies. Melanocytes and fibroblasts express low levels of LPAR1 and are not sensitive to LPAR1i. In contrast, genetic silencing of LPAR1 and pharmacologic inhibition of LPAR1 with HA130, an upstream LPAR1 inhibitor, triggers cell cycle arrest and antitumor activity in MAPKi-resistant cells in vivo. Mechanistically, genetic and pharmacologic targeting of LPAR1 downregulates genes involved in the PI3K/mTOR and Hippo/YAP. Concurrent depletion of YAP and S6K cells significantly impairs melanoma viability relative to knockdown of YAP or S6K alone, suggesting that Hippo/YAP and mTOR/S6K pathways are main downstream effectors of LPAR1 signaling in melanoma. Our data identify novel pathways responsible for the escape of BRAF mutant melanoma from MAPKi therapy, and our hypothesis is that concurrent BRAFi/MEKi/LPAR1i may have therapeutic efficacy. This abstract is also being presented as Poster B02. Citation Format: Vito W. Rebecca, Jianglan Liu, Thomas Connelly, Keith Flaherty, Ze’ev Ronai, Meenhard Herlyn. Comparative screening of skin-derived NCSCs, melanocytes, and melanoma developmental programs reveals LPAR1 in MAPKi resistance [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR18.