Afatinib increases sensitivity to radiation in non-small cell lung cancer cells with acquired EGFR T790M mutation

Oncotarget. 2015 Mar 20;6(8):5832-45. doi: 10.18632/oncotarget.3332.

Abstract

Afatinib is a second-generation of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and has shown a significant clinical benefit in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations. However, the potential therapeutic effects of afatinib combining with other modalities, including ionizing radiation (IR), are not well understood. In this study, we developed a gefitinib-resistant cell subline (PC-9-GR) with a secondary EGFR mutation (T790M) from NSCLC PC-9 cells after chronic exposures to increasing doses of gefitinib. The presence of afatinib significantly increases the cell killing effect of radiation in PC-9-GR cells harboring acquired T790M, but not in H1975 cells with de novo T790M or in H460 cells that express wild-type EGFR. In PC-9-GR cells, afatinib remarkable blocks baseline of EGFR and ERK phosphorylations, and causes delay of IR-induced AKT phosphorylation. Afatinib treatment also leads to increased apoptosis and suppressed DNA damage repair in irradiated PC-9-GR cells, and enhanced tumor growth inhibition when combined with IR in PC-9-GR xenografts. Our findings suggest a potential therapeutic impact of afatinib as a radiation sensitizer in lung cancer cells harboring acquired T790M mutation, providing a rationale for a clinical trial with combination of afatinib and radiation in NSCLCs with EGFR T790M mutation.

Keywords: EGFR; NSCLC; T790M; afatinib; radiosensitization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Afatinib
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / radiation effects
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / radiotherapy*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • ErbB Receptors / genetics*
  • Female
  • Gefitinib
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / radiotherapy*
  • Mice
  • Mice, Nude
  • Mutation*
  • Quinazolines / pharmacology*
  • Radiation-Sensitizing Agents / pharmacology
  • Random Allocation
  • Xenograft Model Antitumor Assays

Substances

  • Quinazolines
  • Radiation-Sensitizing Agents
  • Afatinib
  • EGFR protein, human
  • ErbB Receptors
  • Gefitinib