Enhanced gefitinib‐induced repression of the epidermal growth factor receptor pathway by ataxia telangiectasia‐mutated kinase inhibition in non‐small‐cell lung cancer cells

• Published in: Cancer science 2016-04, Vol.107 (4), p.444-451
• Main Authors: Misumi, Keizo, Sun, Jiying, Kinomura, Aiko, Miyata, Yoshihiro, Okada, Morihito, Tashiro, Satoshi
• Format: Article
• Language: English
• Subjects: AKT protein; Apoptosis; Apoptosis - drug effects; Ataxia; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors; Ataxia Telangiectasia Mutated Proteins - biosynthesis; Ataxia Telangiectasia Mutated Proteins - genetics; ATM inhibitor; Binding sites; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell cycle; Cell growth; Cell Line, Tumor; Cell Proliferation - drug effects; Clinical trials; combination therapy; Cytotoxic agents; Cytotoxicity; Deoxyribonucleic acid; DNA; DNA damage; Drug resistance; Drug Resistance, Neoplasm - genetics; EGFR mutation; EGFR‐TKI; Epidermal growth factor; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; Gefitinib; Growth inhibition; Humans; Insulin; Kinases; Lung cancer; Morpholines - administration & dosage; Mutation; Non-small cell lung carcinoma; non‐small‐cell lung cancer; Original; Phosphorylation; Prognosis; Protein Kinase Inhibitors - administration & dosage; Protein-tyrosine kinase; Pyrones - administration & dosage; Quinazolines - administration & dosage; R&D; Research & development; Signal transduction; Signal Transduction - drug effects
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.12899

The epidermal growth factor receptor (EGFR) tyrosine kinase signaling pathways regulate cellular activities. The 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, some problems, including resistance, remain to be solved. Recently, combination therapy with EGFR‐TKIs and cytotoxic agents has been shown to improve the prognosis of NSCLC patients. To enhance the anticancer effects of EGFR‐TKIs, we examined the cross‐talk 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 anticancer effects against NSCLC cells with the sensitive EGFR mutation. 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.