Overriding adaptive resistance to sorafenib via combination therapy with SHP2 blockade in hepatocellular carcinoma

Abstract

The survival benefit of sorafenib for hepatocellular carcinoma (HCC) patients is unsatisfactory due to the development of adaptive resistance. Increasing evidence has demonstrated that drug resistance can be acquired by cancer cells by activating a number of signaling pathways via receptor tyrosine kinases (RTKs), nevertheless the detailed mechanism for the activation of these alternative pathways is not fully understood. Given the physiological role of Src‐homology 2 domain–containing phosphatase 2 (SHP2) as a downstream effector of many RTKs for activation various signaling cascades, we first found that SHP2 was markedly upregulated in our established sorafenib‐resistant cell lines as well as patient‐derived xenograft (PDTX). Upon sorafenib treatment, adaptive resistance was acquired in HCC cells via activation of RTKs including AXL, EGFR, EPHA2 and IGF1R, leading to RAS/MEK/ERK and AKT reactivation. We found that SHP2 inhibitor SHP099 abrogated sorafenib resistance in HCC cell lines and organoid culture in vitro by blocking this negative feedback mechanism. Interestingly, this sensitization effect was also mediated by induction of cellular senescence. SHP099 in combination with sorafenib was highly efficacious in the treatment of xenografts and genetically engineered models of HCC. In conclusion, SHP2 blockade by SHP099 in combination with sorafenib attenuated the adaptive resistance to sorafenib by impeding RTK‐induced reactivation of the MEK/ERK and AKT signaling pathways. SHP099 in combination with sorafenib may be a novel and safe therapeutic strategy against HCC.