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Overriding Adaptive Resistance to Sorafenib Through Combination Therapy With Src Homology 2 Domain–Containing Phosphatase 2 Blockade in Hepatocellular Carcinoma
Author(s) -
Leung Carmen Oi Ning,
Tong Man,
Chung Katherine Po Sin,
Zhou Lena,
Che Noélia,
Tang Kwan Ho,
Ding Jin,
Lau Eunice Yuen Ting,
Ng Irene Oi Lin,
Ma Stephanie,
Lee Terence Kin Wah
Publication year - 2020
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.30989
Subject(s) - sorafenib , mapk/erk pathway , cancer research , proto oncogene tyrosine protein kinase src , protein kinase b , receptor tyrosine kinase , tyrosine kinase , signal transduction , kinase , epidermal growth factor receptor , medicine , pharmacology , biology , hepatocellular carcinoma , microbiology and biotechnology , receptor
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.