CT-707 Overcomes Resistance of crizotinib through activating PDPK1-AKT1 pathway by targeting FAK.

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.

CONCLUSIONS: These findings indicate that CT-707 may be a promising therapeutic agent against crizotinib-resistance in NSCLC.