MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

Smida, Michal; Fece de la Cruz, Ferran; Kerzendorfer, Claudia; Uras, Iris Z.; Mair, Barbara; Mazouzi, Abdelghani; Suchankova, Tereza; Konopka, Tomasz; Katz, Amanda M.; Paz, Keren; Nagy-Bojarszky, Katalin; Muellner, Markus K.; Bago-Horvath, Zsuzsanna; Haura, Eric B.; Loizou, Joanna I.; Nijman, Sebastian M. B.

doi:10.1038/ncomms13701

Cited by 45Lung Cancer Treatments and MutationsMelanoma and MAPK PathwaysProtein Kinase Regulation and GTPase Signaling

MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

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Smida, Michal, Fece de la Cruz, Ferran, Kerzendorfer, Claudia, Uras, Iris Z., Mair, Barbara, Mazouzi, Abdelghani, Suchankova, Tereza, Konopka, Tomasz +8 more·2016·Nature Communications

DOI 10.1038/ncomms13701PMC PMC5150652

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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.

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In Kras-mutant LUAD mouse models, deleting Atm raises sensitivity to PARP inhibitors, ATR inhibitors, and radiation.
“genetic deletion of Atm is associated with increased sensitivity to poly(ADP-ribose) polymerase (PARP) and ATR inhibitors as well as to radiation therapy in mouse models of Kras-mutant LUAD168, 169.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [169]
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From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [169]

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Abstract PR14: MEK inhibitors block growth of Ataxia Telangiectasia Mutated (ATM) mutant lung tumors
de la Cruz, F. F., Šmída, M., & Nijman, S. M. B. (2017) · Molecular Cancer Therapeutics · doi:10.1158/1538-8514.synthleth-pr14
Self-citation
MEK inhibitors block growth of Ataxia Telangiectasia Mutated (ATM) mutant lung tumors
de la Cruz, F. F., Šmída, M., & Nijman, M. (2017)
P2.03b-069 LKB1 Loss is a Novel Determinant of MEK Sensitivity Due to Alterations in AKT/FOXO3 Signaling
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MEK inhibitor resistance in lung adenocarcinoma is associated with addiction to sustained ERK suppression
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Authors: Smida, M., Fece de la Cruz, F., Kerzendorfer, C., Uras, I. Z., Mair, B., Mazouzi, A., Suchankova, T., Konopka, T., Katz, A. M., Paz, K., Nagy-Bojarszky, K., Muellner, M. K., Bago-Horvath, Z., Haura, E. B., Loizou, J. I., & Nijman, S. M. B.
Affiliations: Austrian Academy of Sciences (AT)
Champions Oncology (United States) (US)
Moffitt Cancer Center (US)
Corresponding author: Nijman, Sebastian M. B.
ORCID: Uras, Iris Z.
Mair, Barbara
Mazouzi, Abdelghani
Konopka, Tomasz
Muellner, Markus K.
Haura, Eric B.
Loizou, Joanna I.
Nijman, Sebastian M. B.
Venue: Nature Communications
Publisher: Springer Science and Business Media LLC
Published: 2016-12-06
Volume: 7
Issue: 1
Pages: 13701-13701
ISSN: 2041-1723 (ISSN-L)
DOI: 10.1038/ncomms13701
PMC: PMC5150652
OpenAlex: W2559957558
Cited by: 44
References: 63
Citations by year: 2026: 2 · 2025: 1 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 8 · 2020: 7 · 2019: 2 · 2018: 5 · 2017: 7
FWCI: 4.17
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (tdm)
creativecommons.org/licenses/by/4.0 (vor)
Locations: Nature Communications (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
ASEP (submittedVersion, public-domain)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: Merck KGaA
European Commission (2007–2013, 321602, FP7 2007-2013, FP7/2007)
Vienna Science and Technology Fund (LS09-009)
Österreichischen Akademie der Wissenschaften
Ministerstvo Školství, Mládeže a Tělovýchovy (CEITEC2020, CZ.1.07/2.3.00/30.0030, LQ1601)
Austrian Science Fund (P24766, P 21768)
Central European Institute of Technology (LQ1601)
FP7 Ideas: European Research Council (311166)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords: MEK inhibitors, trametinib, ataxia telangiectasia, lung adenocarcinoma, synthetic lethality, MEK/ERK signaling, KRAS mutation, BRAF mutation, drug resistance, predictive biomarkers, patient stratification
MeSH terms: Animals, Benzamides, Diphenylamine, Humans, Lung Neoplasms, Mice, Nude, Mutation, Pyridones, Pyrimidinones, Thiophenes, Urea, ras Proteins, Xenograft Model Antitumor Assays, RNA Interference, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Cell Proliferation, Ataxia Telangiectasia Mutated Proteins

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MEK inhibitors block growth of lung tumours with mutations in ataxia–telangiectasia mutated

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