Enhanced gefitinib-induced repression of the EGFR pathway by ATM kinase inhibition in non-small cell lung cancer cells

Summary

The epidermal growth factor receptor (EGFR) tyrosine kinase signaling pathways regulate cellular activities. EGFR tyrosine kinase inhibitors (EGFR-TKIs) repress the EGFR pathway constitutively activated by somatic EGFR gene mutations and have drastically improved the prognosis of non-small cell lung cancer (NSCLC) patients. However, still there are some problems, including resistance, remain to be solved. Recently, the combination therapy with EGFR-TKIs and cytotoxic agents has been shown to improve the prognosis of NSCLC patients. To enhance the anti-cancer effects of EGFR-TKIs, we examined the crosstalk of the EGFR pathways with Ataxia telangiectasia-mutated (ATM) signaling pathways. ATM is a key protein kinase in the DNA damage response and is known to phosphorylate Akt, an EGFR downstream factor. We found that the combination of an ATM inhibitor, KU55933, and an EGFR-TKI, gefitinib, resulted in synergistic cell growth inhibition and induction of apoptosis in NSCLC cell lines carrying the sensitive EGFR mutation. We also found that KU55933 enhanced the gefitinib-dependent repression of the phosphorylation of EGFR and/or its downstream factors. ATM inhibition may facilitate the gefitinib-dependent repression of the phosphorylation of EGFR and/or its downstream factors, to exert anti-cancer effects against NSCLC cells with the sensitive EGFR mutation.

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