Mechanisms of Primary Drug Resistance in FGFR1 -Amplified Lung Cancer
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 -amplified SQLC....
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Veröffentlicht in: | Clinical cancer research 2017-09, Vol.23 (18), p.5527-5536 |
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Zusammenfassung: | 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
-amplified SQLC. However, only about 11% of such
-amplified tumors respond to single-agent FGFR inhibition and several tumors exhibited insufficient tumor shrinkage, compatible with the existence of drug-resistant tumor cells.
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.
The FGFR inhibitor-resistant cells were cross-resistant and characterized by sustained MAPK pathway activation. In drug-resistant H1581 cells, we identified
amplification and
deletion, leading to MAPK pathway reactivation. Furthermore, we detected subclonal
amplifications in 3 of 20 (15%) primary human
-amplified SQLC specimens. In contrast, drug-resistant DMS114 cells exhibited transcriptional upregulation of
that drove MAPK pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.
We provide evidence for the existence of diverse mechanisms of primary drug resistance in
-amplified lung cancer and provide a rational strategy to improve FGFR inhibitor therapies by combination treatment.
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ISSN: | 1078-0432 1557-3265 |
DOI: | 10.1158/1078-0432.CCR-17-0478 |