title: Crizotinib induces PUMA-dependent apoptosis in colon cancer cells.
abstract: Oncogenic alterations in MET or anaplastic lymphoma kinase (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, whereas 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 may be cell type-specific. These findings have important implications for future clinical development of crizotinib.
authors: Department of Pathology, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
authors: Xingnan
authors: X
authors: Zheng
authors: Kan
authors: K
authors: He
authors: Lin
authors: L
authors: Zhang
authors: Jian
authors: J
authors: Yu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism; D000077547:Crizotinib; D004357:Drug Synergism; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D000077157:Sorafenib; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D016159:Tumor Suppressor Protein p53; D009536:Niacinamide; D000077547:Crizotinib; D000077157:Sorafenib; D000077156:Gefitinib