Carmen Oi Ning Leung1, Man Tong2, Katherine Po Sin Chung1, Lena Zhou2, Noélia Che2, Kwan Ho Tang3, Jin Ding4, Eunice Yuen Ting Lau5, Irene Oi Lin Ng6,7, Stephanie Ma2,7, Terence Kin Wah Lee1,8. 1. Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong. 2. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong. 3. Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY. 4. The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Shanghai, China. 5. Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong. 6. Department of Pathology, The University of Hong Kong, Hong Kong. 7. State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong. 8. State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Hong Kong.
Abstract
BACKGROUND AND AIMS: The survival benefit of sorafenib for patients with hepatocellular carcinoma (HCC) 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 through receptor tyrosine kinases (RTKs); nevertheless, the detailed mechanism for the activation of these alternative pathways is not fully understood. APPROACH AND RESULTS: Given the physiological role of Src homology 2 domain-containing phosphatase 2 (SHP2) as a downstream effector of many RTKs for activation of various signaling cascades, we first found that SHP2 was markedly up-regulated in our established sorafenib-resistant cell lines as well as patient-derived xenografts. Upon sorafenib treatment, adaptive resistance was acquired in HCC cells through activation of RTKs including AXL, epidermal growth factor receptor, EPH receptor A2, and insulin-like growth factor 1 receptor, leading to RAS/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), and AKT reactivation. We found that the 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. CONCLUSIONS: 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 safe therapeutic strategy against HCC.
BACKGROUND AND AIMS: The survival benefit of sorafenib for patients with hepatocellular carcinoma (HCC) 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 through receptor tyrosine kinases (RTKs); nevertheless, the detailed mechanism for the activation of these alternative pathways is not fully understood. APPROACH AND RESULTS: Given the physiological role of Src homology 2 domain-containing phosphatase 2 (SHP2) as a downstream effector of many RTKs for activation of various signaling cascades, we first found that SHP2 was markedly up-regulated in our established sorafenib-resistant cell lines as well as patient-derived xenografts. Upon sorafenib treatment, adaptive resistance was acquired in HCC cells through activation of RTKs including AXL, epidermal growth factor receptor, EPH receptor A2, and insulin-like growth factor 1 receptor, leading to RAS/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK), and AKT reactivation. We found that the 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. CONCLUSIONS: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 safe therapeutic strategy against HCC.
Authors: Hao Wang; Wei Hou; Aldeb Perera; Carlee Bettler; Jordan R Beach; Xianzhong Ding; Jun Li; Mitchell F Denning; Asha Dhanarajan; Scott J Cotler; Cara Joyce; Jun Yin; Fowsiyo Ahmed; Lewis R Roberts; Wei Qiu Journal: Cell Rep Date: 2021-02-23 Impact factor: 9.423