FGFR1 Overexpression Identified as a Key Resistance Mechanism to CDK4/6 Inhibitors in ER+ Breast Cancer

The study conducted an ORF kinome screen involving 559 kinase ORF clones in ER+ MCF-7 cells to identify drivers of drug resistance. Among the findings, FGFR1 overexpression was notably linked to reduced sensitivity to CDK4/6 inhibitors, such as fulvestrant and ribociclib. This resistance was observed across various drug concentrations, with FGFR1 overexpression promoting a significant decrease in treatment efficacy.

Further analysis using The Cancer Genome Atlas (TCGA) revealed that 15% of ER+ breast cancers exhibit FGFR1 gene amplification or mRNA overexpression, correlating with early relapse and poor survival rates post-tamoxifen therapy. Experimental models demonstrated that the addition of an FGFR TKI, lucitanib, could reverse this resistance, suggesting a potential therapeutic strategy for overcoming FGFR1-mediated resistance.

In vivo studies with MCF-7FGFR1 xenografts in mice showed that a triple combination therapy of fulvestrant, palbociclib, and lucitanib was significantly more effective in reducing tumor size compared to dual therapy or single treatments. This combination also led to a marked reduction in pharmacodynamic biomarkers of drug action, indicating a restoration of sensitivity to CDK4/6 inhibitors.

The study also explored the role of cyclin D1 (CCND1) in FGFR1-induced drug resistance, finding that CCND1 upregulation is a critical factor in the resistance mechanism. RNA-seq analysis highlighted the suppression of CCND1, among other genes, by the triple combination therapy, further supporting the importance of targeting FGFR1 signaling in overcoming resistance to CDK4/6 inhibitors.

These findings suggest that FGFR1 amplification and overexpression play a significant role in resistance to CDK4/6 inhibitors in ER+ breast cancer. The study proposes the inclusion of FGFR inhibitors in treatment regimens for patients with ER+ breast cancer exhibiting aberrant FGFR signaling, offering a promising avenue for enhancing therapeutic efficacy and overcoming drug resistance.