Crizotinib induces PUMA-dependent apoptosis in colon cancer cells.

Zheng X, He K, Zhang L, Yu J
Mol Cancer Ther. 2013 12 (5): 777-86

PMID: 23427294 · PMCID: PMC3651803 · DOI:10.1158/1535-7163.MCT-12-1146

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.

©2013 AACR

MeSH Terms (23)

Animals Antineoplastic Agents Apoptosis Apoptosis Regulatory Proteins Cell Line, Tumor Colonic Neoplasms Crizotinib Drug Synergism Female Gefitinib Gene Expression Regulation, Neoplastic Humans Mice Niacinamide Phenylurea Compounds Protein Kinase Inhibitors Proto-Oncogene Proteins Pyrazoles Pyridines Quinazolines Sorafenib Tumor Suppressor Protein p53 Xenograft Model Antitumor Assays

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