Elevated expression of RIT1 hyperactivates RAS/MAPK signal and sensitizes hepatocellular carcinoma to combined treatment with sorafenib and AKT inhibitor.

Hyperactivation of RAS/MAPK signaling is commonly observed in hepatocellular carcinoma (HCC). Gain-of-function mutations of canonical RAS genes, however, are rarely detected and it remains unclear how the activity of this pathway is turned on during hepatocarcinogenesis. We performed a comprehensive analysis of RAS superfamily genetic alterations across ten subfamilies, 152 members in 377 HCC patients from the Cancer Genome Atlas database. RIT1 (Ras-like without CAAX 1) was the most frequently altered RAS member amplified in 13% of the HCC cohort. Both genomic amplification and CREB-mediated transcriptional activation contributed to the elevated RIT1 expression, and its overexpression correlated with RAS/MAPK activation and poor prognosis. Then, we found that RIT1-induced angiogenesis via the MEK/ERK/EIF4E/HIF1-α/VEGFA axis. MAP3K11 and MAP3K12, in addition to CRAF, could mediate this process by binding to RIT1. Moreover, RIT1 increased the phosphorylation of p38 MAPK and AKT to promote cell survival under reactive oxygen species stress. Based on this mechanistic understanding, we treated RIT1-overexpressing HCC with combined regimen sorafenib plus AKT inhibitor, and achieved enhanced antitumor effects in vivo. Our study reveals RAS "orphan" member RIT1 as the most common genetic alteration of RAS family in HCC and combination of sorafenib with AKT inhibitor might be a promising treatment strategy for RIT1-overexpressing HCC.