Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations.

Carcinoma, Non-Small-Cell Lung / drug therapy Humans Kelch-Like ECH-Associated Protein 1 Lung Neoplasms / drug therapy MAP Kinase Kinase 1 / genetics Mutation NF-E2-Related Factor 2 Protein-Tyrosine Kinases / genetics Proto-Oncogene Proteins / genetics
MAP2K1 Non-small cell lung cancer mutations therapeutic options

Journal

Lung cancer (Amsterdam, Netherlands)
ISSN: 1872-8332
Titre abrégé: Lung Cancer
Pays: Ireland
ID NLM: 8800805

Informations de publication

Date de publication:
06 2020
Historique:
received: 21 02 2020
revised: 16 04 2020
accepted: 18 04 2020
pubmed: 4 5 2020
medline: 22 6 2021
entrez: 4 5 2020
Statut: ppublish

Résumé

MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive from known driver mutations. Activation of the MEK1-cascade is considered pivotal in resistance to targeted therapy approaches, and MAP2K1 K57 N mutation could be linked to resistance in preclinical models. We set out this study to detect MAP2K1 mutations and potentially targetable co-mutations using a molecular multiplex approach. Between 2012 and 2018, we routinely analyzed 14.512 NSCLC patients with two next-generation sequencing (NGS) panels. In a subset of patients, fluorescence in-situ hybridization was performed to detect rearrangements or amplifications. We assessed clinical parameters and co-occurring mutations and compared treatment outcomes of different forms of systemic therapy. We identified 66 (0.5%) patients with MAP2K1 mutations. Both adenocarcinoma (n = 62) and squamous cell carcinoma (n = 4) histology. The presence of the mutations was linked to smoking, and transversions were more common than transitions. K57 N was the most frequent MAP2K1 mutation (n = 25). Additional mutations were found in 57 patients (86.4%). Mutations of TP53 were detected in 33 patients, followed by KEAP1 mutations in 28.1%. 24 patients (36.4%) had either MAP2K1-only or a co-occurring aberration considered targetable, including EGFR mutations, a BRAF V600E mutation and ROS1 rearrangements. Outcome analyses revealed a trend toward benefit from pemetrexed treatment. Our analysis shows that MAP2K1-mutated NSCLC patients might frequently present with potentially targetable aberrations. Their role in providing resistance in these subtypes and the possible therapeutic opportunities justify further analyses of this rare NSCLC subgroup.

Sections du résumé

BACKGROUND
MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive from known driver mutations. Activation of the MEK1-cascade is considered pivotal in resistance to targeted therapy approaches, and MAP2K1 K57 N mutation could be linked to resistance in preclinical models. We set out this study to detect MAP2K1 mutations and potentially targetable co-mutations using a molecular multiplex approach.
METHODS
Between 2012 and 2018, we routinely analyzed 14.512 NSCLC patients with two next-generation sequencing (NGS) panels. In a subset of patients, fluorescence in-situ hybridization was performed to detect rearrangements or amplifications. We assessed clinical parameters and co-occurring mutations and compared treatment outcomes of different forms of systemic therapy.
RESULTS
We identified 66 (0.5%) patients with MAP2K1 mutations. Both adenocarcinoma (n = 62) and squamous cell carcinoma (n = 4) histology. The presence of the mutations was linked to smoking, and transversions were more common than transitions. K57 N was the most frequent MAP2K1 mutation (n = 25). Additional mutations were found in 57 patients (86.4%). Mutations of TP53 were detected in 33 patients, followed by KEAP1 mutations in 28.1%. 24 patients (36.4%) had either MAP2K1-only or a co-occurring aberration considered targetable, including EGFR mutations, a BRAF V600E mutation and ROS1 rearrangements. Outcome analyses revealed a trend toward benefit from pemetrexed treatment.
CONCLUSION
Our analysis shows that MAP2K1-mutated NSCLC patients might frequently present with potentially targetable aberrations. Their role in providing resistance in these subtypes and the possible therapeutic opportunities justify further analyses of this rare NSCLC subgroup.

Identifiants

DOI: 10.1016/j.lungcan.2020.04.020 PMID: 32361034
pubmed: 32361034
pii: S0169-5002(20)30391-3
doi: 10.1016/j.lungcan.2020.04.020
pii:
doi:

Substances chimiques

Kelch-Like ECH-Associated Protein 1 0
NF-E2-Related Factor 2 0
Proto-Oncogene Proteins 0
Protein-Tyrosine Kinases EC 2.7.10.1
MAP Kinase Kinase 1 EC 2.7.12.2
MAP2K1 protein, human EC 2.7.12.2

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

40-48

Informations de copyright

Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Auteurs

Matthias Scheffler (M)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Alessandra Holzem (A)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Anna Kron (A)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Lucia Nogova (L)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Michaela A Ihle (MA)

University of Cologne, Cologne Institute of Pathology, Cologne, Germany.

Cornelia von Levetzow (C)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Jana Fassunke (J)

University of Cologne, Cologne Institute of Pathology, Cologne, Germany.

Claudia Wömpner (C)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Elisabeth Bitter (E)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Sophia Koleczko (S)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Diana S Y Abdulla (DSY)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Sebastian Michels (S)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Rieke Fischer (R)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Richard Riedel (R)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Jan-Philipp Weber (JP)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Theresa Westphal (T)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany.

Ulrich Gerigk (U)

GFO Clinics Bonn, Marien-Hospital Bonn, Bonn, Germany.

Jens Kern (J)

KWM Missio Clinic, Würzburg, Germany.

Britta Kaminsky (B)

Bethanien Hospital Solingen, Clinic for Pulmonology and Allergology, Solingen, Germany.

Winfried Randerath (W)

Bethanien Hospital Solingen, Clinic for Pulmonology and Allergology, Solingen, Germany.

Karl-Otto Kambartel (KO)

Bethanien Hospital Moers, Lung Center, Moers, Germany.

Sabine Merkelbach-Bruse (S)

University of Cologne, Cologne Institute of Pathology, Cologne, Germany.

Reinhard Büttner (R)

University of Cologne, Cologne Institute of Pathology, Cologne, Germany.

Jürgen Wolf (J)

University Hospital of Cologne, Lung Cancer Group Cologne, Department I of Internal Medicine, Cologne, Germany. Electronic address: juergen.wolf@uk-koeln.de.

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Classifications MeSH

questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Tumeurs des bronches › Carcinome bronchogénique › Carcinome pulmonaire non à petites cellules › Co-occurrence of targetable mutations in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Co-occurrence of targetable mutations in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéine-1 de type kelch associée à ECH › Co-occurrence of targetable mutations in...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Co-occurrence of targetable mutations in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-tyrosine kinases › Mitogen-Activated Protein Kinase Kinases › MAP Kinase Kinase 1 › Co-occurrence of targetable mutations in...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Co-occurrence of targetable mutations in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Facteur-2 apparenté à NF-E2 › Co-occurrence of targetable mutations in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-tyrosine kinases › Co-occurrence of targetable mutations in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › Co-occurrence of targetable mutations in...