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Abstract
Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo. Mechanistically, ATM mediates crosstalk between the prosurvival MEK/ERK and AKT/mTOR pathways. ATM loss also enhances the sensitivity of KRAS- or BRAF-mutant lung cancer cells to MEK inhibition. Thus, ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours.
Highlights
Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed
The serine/threonine kinase ATM is well known for its involvement in the DNA damage response (DDR) and maintaining genome stability but it has been implicated in other cancer-relevant processes including cell growth, metabolism and mitochondrial homeostasis[10]
We compiled a list of 10 tumour suppressor genes that recur in human lung cancer based on publicly available tumour sequencing data and the Catalogue Of Somatic Mutations In Cancer (COSMIC) database[2,4,5,17]
Summary
Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. ATM mutational status in lung cancer is a mechanistic biomarker for MEK inhibitor response, which may improve patient stratification and extend the applicability of these drugs beyond RAS and BRAF mutant tumours. Only a minority of lung tumours harbour mutations in activated kinases such as EGFR, ALK, ROS1 and RET that can be targeted with specific small molecule inhibitors Some of these (for example, gefitinib, erlotinib, crizotinib) have shown moderate success in the clinic, extending survival by several months on average[6,7,8]. The majority of lung cancer mutations, such as ATM (ataxia– telangiectasia mutated) loss-of-function mutations, which are found in 5–10% of patients, are not actionable with smallmolecule inhibitors Some of these so-called ‘undruggable’ mutations may result in vulnerabilities through synthetic lethal interactions that can be exploited with drugs[9]. Our experiments reveal an unexpected link between growth factor signalling pathways and ATM loss, providing a strong rationale for testing MEK inhibitors in the context of ATM mutant tumours
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