Crizotinib Fails to Enhance the Effect of Radiation in Head and Neck Squamous Cell Carcinoma Xenografts.

Mesenchymal-epithelial transition factor (MET), a receptor tyrosine kinase, is expressed in head and neck squamous cell carcinomas (HNSCC) and is involved in tumor progression and associated with poor prognosis. MET can be inhibited by crizotinib, a potent ATP-competitive kinase inhibitor. We examined the effects of combining crizotinib and radiation in a pre-clinical HNSCC model. Nine HNSCC cell lines were screened for MET expression, copy-number amplification and mutational status. The in vitro effects of crizotinib and radiation were assessed with clonogenic survival assays. MET signaling proteins were assessed with western blot and receptor tyrosine kinase array. Tumor growth-delay experiments with UT-SCC-14 and UT-SCC-15 oral tongue xenografts were used to assess in vivo tumor radiosensitivity. All nine HNSCC cell lines showed a varying degree of MET protein and RNA expression. Increased MET copy number was not present. MET was expressed after irradiation both in vitro and in vivo. Crizotinib alone inhibited phosphorylation of MET and inhibited cell growth in vitro but did not inhibit phosphorylation of downstream signaling proteins: MAPK, AKT or c-SRC. When combined with radiation in vitro, crizotinib demonstrated radiation enhancement in only one cell line. Crizotinib did not enhance the effect of radiation in either UT-SCC-14 or UT-SCC-15 tumors grown as xenografts. MET is overexpressed in HNSCC cell lines, however, crizotinib failed to enhance the radiation response and failed to inhibit MET downstream signaling proteins in this HNSCC model.

Baschnagel AM ，Galoforo S ，Thibodeau BJ ，Ahmed S ，Nirmal S ，Akervall J ，Wilson GD ... -  《-》

MET tyrosine kinase inhibitor crizotinib (PF-02341066) shows differential antitumor effects in non-small cell lung cancer according to MET alterations.

Tanizaki J ，Okamoto I ，Okamoto K ，Takezawa K ，Kuwata K ，Yamaguchi H ，Nakagawa K ... -  《-》

HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squamous cell cancer.

Knowles LM ，Stabile LP ，Egloff AM ，Rothstein ME ，Thomas SM ，Gubish CT ，Lerner EC ，Seethala RR ，Suzuki S ，Quesnelle KM ，Morgan S ，Ferris RL ，Grandis JR ，Siegfried JM ... -  《CLINICAL CANCER RESEARCH》

Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells.

Macha MA ，Rachagani S ，Qazi AK ，Jahan R ，Gupta S ，Patel A ，Seshacharyulu P ，Lin C ，Li S ，Wang S ，Verma V ，Kishida S ，Kishida M ，Nakamura N ，Kibe T ，Lydiatt WM ，Smith RB ，Ganti AK ，Jones DT ，Batra SK ，Jain M ... -  《Oncotarget》

Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer.

De Bacco F ，Luraghi P ，Medico E ，Reato G ，Girolami F ，Perera T ，Gabriele P ，Comoglio PM ，Boccaccio C ... -  《-》