Background
Crizotinib has potent anti-tumor activity in patients with advanced MET-amplified non-small cell lung cancer (NSCLC). However, the therapeutic effect is still not satisfying. Thus, developing approaches that improve the efficacy of crizotinib remains a significant challenge.
Methods
MET-amplified NSCLC cell lines were treated with crizotinib and cyclosporine A (CsA). Cell viability was determined by MTS assay. The changes of apoptosis, cell cycle and calcineurin-Erk pathways were assessed by western blot. Xenograft mouse model, primary human NSCLC cells and hollow fiber assays were utilized to confirm the effects of CsA. Findings: We demonstrated that CsA significantly increased the anti-tumor effect of crizotinib on multiple MET-amplified NSCLC cells in vitro and in vivo. Mechanistically, crizotinib treatment led to the activation of Ca2+-calcineurin (CaN)-Kinase suppressor of Ras 2 (KSR2) signaling, resulting in Erk1/2 activation and enhanced survival of cancer cells. CsA effectively blocked CaN-KSR2-Erk1/2 signaling, promoting crizotinib-induced apoptosis and G2/M arrest. Similarly, pharmacologic or genetic inhibition of Erk1/2 also enhanced crizotinib-induced growth inhibition in vitro. Xenograft studies further confirmed that CsA or Erk1/2 inhibitor PD98059 enhanced the anti-cancer activity of crizotinib through inhibition of CaN-Erk1/2 axis. The