Universität zu Köln

Malchers, Florian, Ercanoglu, Meryem, Schuette, Daniel ORCID: 0000-0002-4746-537X, Castiglione, Roberta ORCID: 0000-0002-9828-4405, Tischler, Verena ORCID: 0000-0002-6673-8329, Michels, Sebastian, Dahmen, Ilona, Braegelmann, Johannes, Menon, Roopika, Heuckmann, Johannes M., George, Julie, Ansen, Sascha, Sos, Martin L., Soltermann, Alex, Peifer, Martin ORCID: 0000-0002-5243-5503, Wolf, Juergen, Buettner, Reinhard and Thomas, Roman K. (2017). Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer. Clin. Cancer Res., 23 (18). S. 5527 - 5537. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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Abstract

Purpose: The 8p12-p11 locus is frequently amplified in squamous cell lung cancer (SQLC); the receptor tyrosine kinase fibroblast growth factor receptor 1 (FGFR1) being one of the most prominent targets of this amplification. Thus, small molecules inhibiting FGFRs have been employed to treat FGFR1-amplified SQLC. However, only about 11% of such FGFR1-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells. Experimental Design: To investigate possible mechanisms of resistance to FGFR inhibition, we studied the lung cancer cell lines DMS114 and H1581. Both cell lines are highly sensitive to three different FGFR inhibitors, but exhibit sustained residual cellular viability under treatment, indicating a subpopulation of existing drug-resistant cells. We isolated these subpopulations by treating the cells with constant high doses of FGFR inhibitors. Results: The FGFR inhibitor-resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified NRAS amplification and DUSP6 deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal NRAS amplifications in 3 of 20 (15%) primary human FGFR1-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of MET that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors. Conclusions: We provide evidence for the existence of diverse mechanisms of primary drug resistance in FGFR1-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment. (C) 2017 AACR.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Malchers, Florian UNSPECIFIED UNSPECIFIED UNSPECIFIED Ercanoglu, Meryem UNSPECIFIED UNSPECIFIED UNSPECIFIED Schuette, Daniel UNSPECIFIED orcid.org/0000-0002-4746-537X UNSPECIFIED Castiglione, Roberta UNSPECIFIED orcid.org/0000-0002-9828-4405 UNSPECIFIED Tischler, Verena UNSPECIFIED orcid.org/0000-0002-6673-8329 UNSPECIFIED Michels, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Dahmen, Ilona UNSPECIFIED UNSPECIFIED UNSPECIFIED Braegelmann, Johannes UNSPECIFIED UNSPECIFIED UNSPECIFIED Menon, Roopika UNSPECIFIED UNSPECIFIED UNSPECIFIED Heuckmann, Johannes M. UNSPECIFIED UNSPECIFIED UNSPECIFIED George, Julie UNSPECIFIED UNSPECIFIED UNSPECIFIED Ansen, Sascha UNSPECIFIED UNSPECIFIED UNSPECIFIED Sos, Martin L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Soltermann, Alex UNSPECIFIED UNSPECIFIED UNSPECIFIED Peifer, Martin UNSPECIFIED orcid.org/0000-0002-5243-5503 UNSPECIFIED Wolf, Juergen UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Thomas, Roman K. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-217668
DOI:	10.1158/1078-0432.CCR-17-0478
Journal or Publication Title:	Clin. Cancer Res.
Volume:	23
Number:	18
Page Range:	S. 5527 - 5537
Date:	2017
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1557-3265
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RECEPTOR TYROSINE KINASE; ADVANCED SOLID TUMORS; SELECTIVE INHIBITOR; ACQUIRED-RESISTANCE; DOSE-ESCALATION; PHASE-I; AMPLIFICATION; GEFITINIB; POTENT; CRIZOTINIB Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/21766