title: Effect of PF-02341066 and radiation on non-small cell lung cancer cells.
abstract: Recently, a fusion protein of echinoderm microtubule associated protein             like-4 (EML4) and anaplastic lymphoma kinase (ALK) has been found in non-small             cell lung cancer (NSCLC) patients. In addition, endogenous expression of phosphorylated             c-Met was found to be increased in many invasive NSCLC cases. PF-02341066 (crizotinib)             is a novel dual c-Met and EML4-ALK inhibitor, and preclinical studies have shown             that treatment with ALK inhibitors leads to drastic tumor regression in xenograft             models. A phase I trial of PF-02341066 yielded a 53% response rate and a disease             control rate of 79%. We evaluated crizotinib as a potential radiation-sensitizing             agent in multiple established NSCLC cell lines with varying expression levels             of c-Met and EML4-ALK. The combined effect of ionizing radiation (IR) and PF-02341066             was determined by the surviving cell fraction, cell cycle distribution, apoptosis,             DNA double-strand break repair in 5 NSCLC cell lines (A549, H460, H3122, H2228             and H1993) and in in vivo xenograft studies. Treatment of NSCLC cells with either             PF-02341066 alone or PF-02341066 + IR did not significantly alter cellular radiosensitivity,             DNA repair kinetics and cell cycle distribution; no significant enhancement of             tumor growth delay was noted in response to the combined treatment of PF-02341066 + IR.             EML4-ALK and c-Met inhibition leads to activation of parallel pathways that converge             on Akt signaling which abrogates any radiation-sensitizing effect. Although PF-02341066             is an effective therapy able to suppress tumor growth in tumors that exhibit positivity             for either EML4-ALK or c-Met, it did not affect the intrinsic radiation response             of tumor cell lines. In the present study, we demonstrated that PF-02341066 did             not enhance radiation sensitivity in a panel of NSCLC cell lines.
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern                     Medical Center, Dallas, TX 75390, USA.
authors.forename: Vasu
authors.initials: V
authors.lastname: Tumati
authors.forename: Subashri
authors.initials: S
authors.lastname: Kumar
authors.forename: Lan
authors.initials: L
authors.lastname: Yu
authors.forename: Benjamin
authors.initials: B
authors.lastname: Chen
authors.forename: Hak
authors.initials: H
authors.lastname: Choy
authors.forename: Debabrata
authors.initials: D
authors.lastname: Saha
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D059248:Chemoradiotherapy; D000077547:Crizotinib; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011720:Pyrazoles; D011725:Pyridines; D011838:Radiation-Sensitizing Agents; D000077547:Crizotinib