Effect of PF-02341066 and radiation on non-small cell lung cancer cells

Vasu Tumati, Subashri Kumar, Lan Yu, Benjamin Chen, Hak Choy, Debabrata Saha

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Recently, a fusion protein of echinoderm micro-tubule 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.

Original languageEnglish (US)
Pages (from-to)1094-1100
Number of pages7
JournalOncology reports
Volume29
Issue number3
DOIs
StatePublished - Mar 1 2013

Keywords

  • ALK inhibitors
  • Animal models
  • DNA double-strand break repair
  • Non-small cell lung cancer
  • Radiation resistance
  • Radio-sensitization
  • Tumor growth delay

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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