Mechanisms of primary drug resistance in FGFR1 amplified lung cancer

Purpose: <br />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.<br />Experimental Design: <br />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.<br />Results: <br />The FGFR inhibitor resistant cells were cross-resistant and characterized by sustained mitogen-activated protein kinase (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 out of 20 (15%) primary human FGFR1 amplified SQLC specimens. By contrast, drug resistant DMS114 cells exhibited transcriptional up-regulation of MET that drove MAPK-pathway reactivation. As a consequence, we demonstrate that rational combination therapies resensitize resistant cells to treatment with FGFR inhibitors.<br />Conclusions:<br />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.

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