Efficacy of focal adhesion kinase inhibition in non small cell lung cancer with oncogenically activated MAPK pathways
Background:Focal adhesion kinase (FAK) is overexpressed in many types of tumours, including lung cancer. Y15, a small molecule which inhibits Y397 FAK autophosphorylation, decreases growth of human neuroblastoma, breast and pancreatic cancers. In this study, we investigated the in vitro and in vivo effects of Y15, and the underlying mechanism on non small cell lung cancer cells.Methods:The cytotoxic effects of Y15 targeting FAK signalling were evaluated. Gene knockdown experiments were performed to determine the anti cancer mechanism. Xenografts with RAS or EGFR mutations were selected for in vivo Y15 treatment.Results:Y15 blocked autophosphorylation of FAK in a time and dose dependent manner. It caused dose dependent decrease of lung cancer cell viability and clonogenicity. Y15 inhibited tumour growth of RAS mutant (A549 with KRAS mutation and H1299 with NRAS mutation) as well as epidermal growth factor receptor (EGFR) mutant (H1650 and H1975) lung cancer xenografts. JNK activation is a mechanism underlying Y15 induced Bcl 2 and Mcl 1 downregulation. Moreover, knockdown of Bcl 2 or Bcl xL potentiated the effects of Y15. The combination of various inhibitors of the Bcl 2 family of proteins with FAK inhibitors demonstrated synergy in multiple lung cancer cell lines in vitro.Conclusions:FAK inhibition demonstrated efficacy both in vitro and in vivo in lung cancers with either oncogenic RAS or EGFR mutations. In addition, FAK inhibition in combination with inhibitors of Bcl 2 family of anti apoptotic proteins has synergistic activity in these MAPK activated non small cell lung cancer cell line models.
British Journal of Cancer