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CT-707 Overcomes Resistance of Crizotinib through Activating PDPK1- AKT1 Pathway by Targeting FAK

[ Vol. 18 , Issue. ]

Author(s):

Caixia Liang, Ningning Zhang, Qiaoyun Tan, Shuxia Liu, Rongrong Luo, Yanrong Wang, Yaunkai Shi* and Xiaohong Han*Pages 1-11 (11)

Abstract:


Background: Crizotinib established the position of anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKI) in the treatment of non-small cell lung cancer (NSCLC) while the therapy- resistance hindered those patients from benefitting continuously from the treatment. CT-707 is an inhibitor of ALK/focal adhesion kinase (FAK) and IGFR-1. H2228CR (crizotinib resistance, CR) and H3122CR NSCLC cell lines were generated from the parental cell line H2228 (EML4-ALK, E6a/b:A20, variant 3) and H3122(EML4-ALK, E13:A20, variant 1), respectively. Methods: We investigated the antitumor effects CT-707 exerted against H3122CR in vitro /vivo. Results: Importantly, our study provided evidence that CT-707 overcomes resistance to crizotinib through activating PDPK1-AKT1 pathway by targeting FAK. Meanwhile, by using an in-vivo H3122CR xenograft model, we found CT-707 inhibited tumor growth significantly without obvious side effects. Conclusion: These findings indicate that CT-707 may be a promising therapeutic agent against crizotinib- resistance in NSCLC.

Keywords:

anaplastic lymphoma kinase, CT-707, crizotinib resistance, non-small cell lung cancer.

Affiliation:

Department of Medical Oncology, Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100021, Department of Medical Oncology, Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100021, Department of Medical Oncology, Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100021, Department of Medical Oncology, Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100021, Department of Medical Oncology, Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100021, Department of Medical Oncology, Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100021, Department of Medical Oncology, Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences , Beijing 100021, Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100021



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