Co-occurrence of targetable aberrations in non-small cell lung cancer patients harboring MAP2K1 mutations
| Autor: | Juergen Wolf, Rieke Fischer, Anna Kron, Karl-Otto Kambartel, Joachim Lorenz, Matthias Scheffler, Lucia Nogova, Sabine Merkelbach-Bruse, Sebastian Michels, Britta Kaminsky, Reinhard Büttner, Claudia Wompner, Michaela Angelika Ihle, Elisabeth Bitter, Ulrich Gerigk, Alessandra Holzem, Winfried Randerath, Jens Kern |
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| Rok vydání: | 2017 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 35:e20059-e20059 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | e20059 Background: MAP2K1 mutations are rare in non-small cell lung cancer (NSCLC) and considered to be mutually exclusive with known driver mutations. Activation of the MEK1-cascade might play a pivotal role in resistance to targeted inhibition of BRAF V600E, EML4-ALK and EGFR T790M. So far, however, only MAP2K1 K57N could be identified and linked functionally to resistance in preclinical models. Clinical trials combining specific inhibitors for predefined NSCLC subgroups with MEK inhibitors are ongoing. We sought to characterize frequency and type of MAP2K1-mutated NSCLC regarding curated targetable aberrations. Methods: Tumor tissue collected consecutively from 4590 NSCLC patients within the German Network Genomic Medicine (NGM) between 07/2014 and 07/2015 was analyzed for MAP2K1 mutations using next-generation sequencing (NGS) with a set of 102 amplicons in 14 genes. Clinical and molecular characteristics of these patients were determined and compared with an internal control group of NSCLC patients and an independent control group of The Cancer Genome Atlas (TCGA). Results: We identified 21 (0.5%) patients with MAP2K1 mutations. They were frequently found in adenocarcinomas (n = 20) and were significantly associated with smoking. The most common MAP2K1 mutation was K57N. Most of the patients (n = 16) had additional oncogenic driver aberrations, including mutations in ALK, EGFR or BRAF, ROS1 rearrangements and MET amplification. TP53 mutations were found in 11 patients. In only five patients (23.8%) MAP2K1 occurred exclusively. TCGA analysis revealed additional 10 patients with MAP2K1 mutations, whereof 9 had additional TP53 mutations and one had BRAF mutation. Whereof most patients in our cohort had stage IV NSCLC, all patients in TCGA were systemic treatment naive. Compared with local stages in TCGA, our findings strongly suggest that targetable co-occurring mutations might occur more frequently in advanced stage NSCLC patients. Conclusions: MAP2K1 mutations co-occur frequently with targetable aberrations in smoking stage IV patients. Combination of targeted therapy against known driver aberrations with MEK inhibitors might be a promising therapeutic approach for such patients. |
| Databáze: | OpenAIRE |
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