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

Curr Cancer Drug Targets. 2019;19(8):655-665. doi: 10.2174/1568009618666181031152140.

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.

Trial registration: ClinicalTrials.gov NCT02695550.

Keywords: Anaplastic lymphoma kinase; CT-707; crizotinib resistance; non-small cell lung cancer; therapeutic agent; xenograft model..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Phosphoinositide-Dependent Protein Kinases / genetics
  • 3-Phosphoinositide-Dependent Protein Kinases / metabolism*
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Cycle
  • Cell Proliferation
  • Crizotinib / pharmacology*
  • Female
  • Focal Adhesion Kinase 1 / antagonists & inhibitors*
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Crizotinib
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • 3-Phosphoinositide-Dependent Protein Kinases
  • AKT1 protein, human
  • PDPK1 protein, human
  • Proto-Oncogene Proteins c-akt

Associated data

  • ClinicalTrials.gov/NCT02695550