Nanoparticles Targeting Raf/Erk-Driven Cell-Autonomous Resistance To Sorafenib For Effective Treatment Of Hepatocellular Carcinoma

Sorafenib is the only systemic therapy approved for advanced hepatocellular carcinoma (HCC). Sorafenib9s efficacy has been attributed in part to inhibition of cancer cell proliferation due to B- and CRAF targeting in HCC cells. However, cell autonomous mechanisms promote evasion from sorafenib treatment, leading to moderate survival benefit. Herein, we demonstrated that the effects of sorafenib on HCC cell viability were initially independent of RAF kinase inhibition and were mediated in part by p38MAPK inhibition. Moreover, sorafenib treatment led to RAF heterodimerization (BRAF/CRAF) and subsequent ERK activation and thus converted HCC cell dependence for survival signaling to the RAF/ERK pathway. Inhibition of ERK pathway by the MEK inhibitor AZD6244 significantly enhanced the therapeutic efficacy of sorafenib efficacy on HCC in vitro and in vivo. Furthermore, we developed HCC-targeted nanoparticles (NPs) to efficiently co-deliver both sorafenib and AZD6244 into HCC, downregulate RAF/ERK pathway, suppress angiogenesis and enhance anti-cancer effect in the orthotopic HCC model. In conclusion, sorafenib treatment leads to rapid MAPK activation due to BRAF heterodimerization as a cell-autonomous mechanism of treatment resistance. Co-delivery of sorafenib and MEK inhibitor AZD6244 using HCC targeted NPs downregulates the compensatory activated RAF/ERK pathway and overcomes resistance to sorafenib in HCC. Citation Format: Yunching Chen, Ya-Chi Liu, Ts-Ting Lin, Rakesh Ramjiawan, Dan Duda. Nanoparticles targeting RAF/ERK-driven cell-autonomous resistance to sorafenib for effective treatment of hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1315.