Abstract 901: Antibody-mediated blockade of annexin A3 (ANXA3) synergistically enhances the efficacy of sorafenib and regorafenib for hepatocellular carcinoma

Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Sorafenib is the only FDA approved first-line targeted drug for advanced HCC, but its effect on patients9 survival gain is limited and patients ultimately present disease progression. Molecular mechanism underlying acquired resistance are still far from being well understood. A better understanding of causes of sorafenib resistance, enhancing the efficacy of sorafenib and finding a reliable predictive biomarker are crucial to achieve efficient control of HCC. In this study, we uncovered a role of annexin A3 (ANXA3) in conferring ability of HCC cells to resist sorafenib. ANXA3 was found highly enriched in sorafenib-resistant HCC cells and patient-derived xenografts. Mechanistically, we found overexpression of ANXA3 in sorafenib-resistant HCC cells to suppress PKCδ/p38 associated apoptosis and activate autophagy for cell survival. ANXA3 expression correlated positively with LC3B, an indicator of autophagy induction, in HCC specimens and was associated with a worst overall survival in HCC patients who went on to receive sorafenib treatment. Anti-ANXA3 therapy, alone or combined with sorafenib and regorafenib, the standard of care for advanced HCC, impaired tumor growth in vivo and significantly increased survival. In sum, we found anti-ANXA3 therapy to exhibit abilities to reduce tumor growth and sensitize HCC cells to sorafenib and regorafenib treatment via suppressing autophagy and activating apoptosis. Inhibition of ANXA3 would benefit a subset of patients after sorafenib progression. ANXA3 can also serve as a useful predictive biomarker for patient response to sorafenib treatment. Citation Format: Man Tong, Noelia Che, Lei Zhou, Phillis W. Kau, Steve T. Luk, Xin Chen, Jin Ding, Terence K. Lee, Stephanie Ma. Antibody-mediated blockade of annexin A3 (ANXA3) synergistically enhances the efficacy of sorafenib and regorafenib for hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 901.