Universität zu Köln

Scheffler, Matthias, Holzem, Alessandra, Kron, Anna, Nogova, Lucia, Ihle, Michaela A., von Levetzow, Cornelia, Fassunke, Jana, Woempner, Claudia, Bitter, Elisabeth, Koleczko, Sophia, Abdulla, Diana S. Y., Michels, Sebastian, Fischer, Rieke, Riedel, Richard, Weber, Jan-Philipp, Westphal, Theresa, Gerigk, Ulrich, Kern, Jens, Kaminsky, Britta, Randerath, Winfried, Kambartel, Karl-Otto, Merkelbach-Bruse, Sabine, Buttner, Reinhard and Wolf, Juergen (2020). Co-occurrence of targetable mutations in Non-small cell lung cancer (NSCLC) patients harboring MAP2K1 mutations. Lung Cancer, 144. S. 40 - 49. CLARE: ELSEVIER IRELAND LTD. ISSN 1872-8332

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Scheffler, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Holzem, Alessandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Kron, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Nogova, Lucia UNSPECIFIED UNSPECIFIED UNSPECIFIED Ihle, Michaela A. UNSPECIFIED UNSPECIFIED UNSPECIFIED von Levetzow, Cornelia UNSPECIFIED UNSPECIFIED UNSPECIFIED Fassunke, Jana UNSPECIFIED UNSPECIFIED UNSPECIFIED Woempner, Claudia UNSPECIFIED UNSPECIFIED UNSPECIFIED Bitter, Elisabeth UNSPECIFIED UNSPECIFIED UNSPECIFIED Koleczko, Sophia UNSPECIFIED UNSPECIFIED UNSPECIFIED Abdulla, Diana S. Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Michels, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Fischer, Rieke UNSPECIFIED UNSPECIFIED UNSPECIFIED Riedel, Richard UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Jan-Philipp UNSPECIFIED UNSPECIFIED UNSPECIFIED Westphal, Theresa UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerigk, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Kern, Jens UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaminsky, Britta UNSPECIFIED UNSPECIFIED UNSPECIFIED Randerath, Winfried UNSPECIFIED UNSPECIFIED UNSPECIFIED Kambartel, Karl-Otto UNSPECIFIED UNSPECIFIED UNSPECIFIED Merkelbach-Bruse, Sabine UNSPECIFIED UNSPECIFIED UNSPECIFIED Buttner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolf, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-332387
DOI:	10.1016/j.lungcan.2020.04.020
Journal or Publication Title:	Lung Cancer
Volume:	144
Page Range:	S. 40 - 49
Date:	2020
Publisher:	ELSEVIER IRELAND LTD
Place of Publication:	CLARE
ISSN:	1872-8332
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ACQUIRED-RESISTANCE; GENOMIC ALTERATIONS; SQUAMOUS-CELL; PHASE-II; ADENOCARCINOMA; CHEMOTHERAPY; KRAS; TRAMETINIB; CRIZOTINIB; THERAPY Multiple languages Oncology; Respiratory System Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33238