Crizotinib induces PUMA-dependent apoptosis in colon cancer cells
Menée sur des lignées cellulaires et à l'aide de xénogreffes de tumeurs du côlon, cette étude met en évidence un mécanisme par lequel le crizotinib induit une apoptose des cellules cancéreuses
Oncogenic alterations in MET or ALK have been identified in a variety of human cancers. Crizotinib (PF02341066) is a dual MET and ALK inhibitor and approved for the treatment of a subset of non-small-cell lung carcinoma; and in clinical development for other malignancies. Crizotinib can induce apoptosis in cancer cells while the underlying mechanisms are not well understood. In this study, we found that crizotinib induces apoptosis in colon cancer cells through the BH3-only protein PUMA. In cells with wild-type p53, crizotinib induces rapid induction of PUMA and Bim accompanied by p53 stabilization and DNA damage response. The induction of PUMA and Bim is mediated largely by p53, and deficiency in PUMA or p53, but not Bim, blocks crizotinib-induced apoptosis. Interestingly, MET knockdown led to selective induction of PUMA, but not Bim or p53. Crizotinib also induced PUMA-dependent apoptosis in p53-deficient colon cancer cells, and synergized with gefitinib or sorafenib to induce marked apoptosis via PUMA in colon cancer cells. Furthermore, PUMA deficiency suppressed apoptosis and therapeutic responses to crizotinib in xenograft models. These results establish a critical role of PUMA in mediating apoptotic responses of colon cancer cells to crizotinib, and suggest that mechanisms of oncogenic addiction to MET/ALK-mediated survival might be cell-type specific. These findings have important implications for future clinical development of crizotinib.
http://mct.aacrjournals.org/content/early/2013/02/20/1535-7163.MCT-12-1146.abstract