Abstract
Mutations in the Ataxia-telangiectasia mutated (ATM) gene are frequently found in human cancers, including non-small cell lung cancer (NSCLC). Loss of ATM function confers sensitivity to ionising radiation (IR) and topoisomerase inhibitors and may thus define a subset of cancer patients that could get increased benefit from these therapies. In this study, we evaluated the phenotypic consequences of ATM missense changes reported in seven NSCLC cell lines with regard to radiosensitivity and functionality of ATM signalling. Our data demonstrate that only 2/7 NSCLC cell lines (H1395 and H23) harbouring ATM missense mutations show a functional impairment of ATM signalling following IR-exposure. In these two cell lines, the missense mutations caused a significant reduction in ATM protein levels, impairment of ATM signalling and marked radiosensitivity. Of note, only cell lines with homozygous mutations in the ATM gene showed significant impairment of ATM function. Based on these observations, we developed an immunohistochemistry-based assay to identify patients with loss or reduction of ATM protein expression in a clinical setting. In a set of 137 NSCLC and 154 colorectal cancer specimens we identified tumoral loss of ATM protein expression in 9.5% and 3.9% of cases, respectively, demonstrating the potential utility of this method.
Highlights
Lung cancer is the most common cancer type and, at the same time, has one of the lowest survival outcomes, rendering it the leading cause of cancer-related mortality worldwide [1]
Ataxiatelangiectasia mutated (ATM) missense mutations found in non-small cell lung cancer (NSCLC) can lead to a reduction in ATM protein levels and impairment of the ATM signalling pathway
Somatic mutations in the ATM gene have been identified in a range of cancer types, including NSCLC, and in several established and widely used NSCLC cell lines [22,23,24]
Summary
Lung cancer is the most common cancer type and, at the same time, has one of the lowest survival outcomes, rendering it the leading cause of cancer-related mortality worldwide [1]. Most lung cancer patients are treated with DNA-damaging modalities such as chemotherapy and ionising radiation (IR) Effective, these treatments generally lack selectivity towards cancer cells resulting in normal tissue toxicity and potentially severe side effects, which are limiting factors for both the dose and duration of therapy [2, 3]. Germline mutations in the ATM gene are responsible for the autosomal recessive human hereditary disorder Ataxia-telangiectasia (AT). This disease, caused by a loss of ATM function, is characterised by progressive cerebellar degeneration, telangiectasia, immunodeficiency, growth retardation, genomic instability, cancer susceptibility and profound sensitivity to IR [4, 7,8,9]. Considering the substantial www.impactjournals.com/oncotarget sensitivity to IR, radiomimetic drugs and topoisomerase inhibitors observed in cells derived from A-T patients [7, 16, 17], tumoral loss of ATM function may define a subset of patients that could get increased benefit from such treatments
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