索拉非尼
MAPK/ERK通路
癌症研究
原癌基因酪氨酸蛋白激酶Src
蛋白激酶B
肝细胞癌
受体酪氨酸激酶
医学
酪氨酸激酶
信号转导
激酶
表皮生长因子受体
药理学
生物
内科学
细胞生物学
受体
作者
Chun Sing Leung,Man Tong,Katherine Po Sin Chung,Lena Zhou,Noélia Che,Kwan Ho Tang,Jin Ding,Eunice Y. Lau,Irene Oi Lin Ng,Stephanie Ma,Terence Lee
出处
期刊:Hepatology
[Wiley]
日期:2020-03-31
卷期号:72 (1): 155-168
被引量:60
摘要
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.
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