Abstract 773: Crizotinib (PF-02341066) reverses multidrug resistance in cancer cells by inhibiting the function of P-glycoprotein

Abstract

Abstract Background and purpose: Besides targeting the well-known oncogenic c-Met, crizotinib is the first oral tyrosine kinase inhibitor (TKI) inhibiting anaplastic lymphoma kinase (ALK) in clinical trials for the treatment of non-small cell lung cancer (NSCLC). In this study, we investigated the potential multidrug resistance (MDR) reversal by crizotinib in vitro and in vivo. Experimental approach: MTT methods were used in vitro and the xenografts in nude mice were used in vivo to investigate crizotinib reversal of MDR. To understand the mechanisms for MDR reversal, the alterations of intracellular doxorubicin(Dox) or rhodamine 123 accumulation, Dox effluxion, ABCB1 expression level, ATPase activity of ABCB1, and crizotinib-induced c-Met, Akt and Erk1/2 phosphorylation were examined. Key results: Crizotinib significantly enhanced the cytotoxicity of ABCB1 substrate chemotherapeutic agents in MDR cells, with no effect found on sensitive cells in vitro and in vivo. In addition, crizotinib significantly increased the intracellular accumulation of rhodamine 123 and doxorubicin and inhibited the drug efflux in ABCB1-overexpressing MDR cells. Further studies showed that crizotinib enhanced the ATPase activity of ABCB1 in concentration-dependent manner. However, the expressions of ABCB1 were not affected and the reversal activity of crizotinib was not related to the phosphorylation of c-Met, Akt or Erk1/2. Importantly, crizotinib significantly enhanced the effect of paclitaxel against the KBv200 cell xenografts in nude mice. Conclusions and implications: Crizotinib was found to reverse ABCB1-mediated MDR by inhibiting ABCB1 transport function without involvement of ABCB1 expression or blockade of the Akt or Erk1/2 pathways. These findings is useful for combination chemotherapy of crizotinib with conventional chemotherapeutic drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 773. doi:1538-7445.AM2012-773