Reference Detail

Ref Type

Journal Article

PMID

(28630215)

Authors

Malchers F, Ercanoglu M, Schütte D, Castiglione R, Tischler V, Michels S, Dahmen I, Brägelmann J, Menon R, Heuckmann JM, George J, Ansén S, Sos ML, Soltermann A, Peifer M, Wolf J, Büttner R, Thomas RK

Title

Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	23	18	2017 Sep 15	5527-5536	Clin Cancer Res

URL

Abstract Text

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. Clin Cancer Res; 23(18); 5527-36. ©2017 AACR.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
FGFR1 amp	lung non-small cell carcinoma	sensitive	Infigratinib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Truseltiq (infigratinib) and Mekinist (trametinib) combination treatment inhibited Erk signaling and growth of FGFR1-amplified non-small cell lung carcinoma cells in culture (PMID: 28630215).	28630215
FGFR1 amp NRAS over exp	lung non-small cell carcinoma	sensitive	Infigratinib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Truseltiq (infigratinib) and Mekinist (trametinib) combination treatment inhibited Erk signaling, resulting in growth inhibition in FGFR1-amplified non-small cell lung carcinoma cells overexpressing Nras in culture (PMID: 28630215).	28630215
FGFR1 amp NRAS over exp	lung non-small cell carcinoma	decreased response	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, overexpression of Nras in FGFR1-amplified non-small cell lung carcinoma cells resulted in decreased response to Truseltiq (infigratinib) in culture (PMID: 28630215).	28630215
FGFR1 amp NRAS amp	lung non-small cell carcinoma	resistant	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, amplification of NRAS was identified in a non-small cell lung cancer cell line harboring FGFR1 amplification that acquired resistance to Truseltiq (infigratinib) in culture (PMID: 28630215).	28630215
FGFR1 amp NRAS amp	lung non-small cell carcinoma	sensitive	Infigratinib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Truseltiq (infigratinib) and Mekinist (trametinib) combination treatment inhibited Erk signaling, resulting in growth inhibition in non-small cell lung carcinoma cells harboring both FGFR1 and NRAS amplification in culture (PMID: 28630215).	28630215
FGFR1 amp	lung non-small cell carcinoma	sensitive	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Truseltiq (infigratinib) inhibited Erk signaling and growth of FGFR1-amplified non-small cell lung carcinoma cells in culture (PMID: 28630215).	28630215
FGFR1 amp NRAS amp	lung non-small cell carcinoma	resistant	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, non-small cell lung carcinoma cells harboring both FGFR1 and NRAS amplification were resistant to Mekinist (trametinib) in culture (PMID: 28630215).	28630215