Mechanisms of Primary Drug Resistance in FGFR1-Amplified Lung Cancer

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.

Recent updates on the resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors and resistance reversion strategies in lung cancer

“…109 In addition, treatment with FGFR inhibitors restored the sensitivity to EGFR-TKIs in primary drug-resistant SCLC cells. 110 Therefore, FGFR activation is one of the possible causes of developed resistance to EGFR-TKIs in lung cancer patients. and sensitivity to gefitinib and erlotinib were restored in clones derived from PC-9/GEF1-1 and PC-9/GEF2-1.…”

Mechanisms of acquired resistance to fibroblast growth factor receptor targeted therapy

“…Bypass signaling can also occur due to changes within the PI3K/AKT/mTOR [55][56][57] , MAPK [50,58,59] , STAT3 [60] and GSK3β [61] signaling pathways. Increased PI3K/AKT/mTOR signaling, independent of changes in upstream receptor tyrosine kinases has been described in DMS114 lung cancer cells (FGFR1 amplified) and RT112 urothelial cancer cells (FGFR3-TACC3) following chronic treatment with infigratinib [56] .…”

The Secretome Engages STAT3 to Favor a Cytokine-rich Microenvironment in Mediating Acquired Resistance to FGFR Inhibitors

“…Although one report showed that NRAS and c-Met account for resistance in NCI-H1581 cells and treated these changes as a primary resistance mechanism, we did not observe similar results here. In addition, in contrast to our gradient of inhibitor concentrations, this report used long exposure times to obtain resistant clones, which we believed still reflected acquired rather than primary resistance responses (32).…”