HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2

Abstract

Purpose Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2+) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab. Experimental Design HER2+ BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings and a novel drug combination was tested against LTR xenografts. Gene expression and copy number analyses were performed to corroborate our findings in clinical samples. Results LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro. Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2+ early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathological complete response in patients with HER2+ early breast cancer treated with neoadjuvant anti-HER2 therapy. Conclusions Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors.

Fibroblast growth factor receptor facilitates recurrence of minimal residual disease following trastuzumab emtansine therapy

“…2B). These data are consistent with recent findings that indicate the BT474 model amplifies the genomic cluster of FGF ligands 3/4/19 instead of modulating FGF receptors (18). To elucidate if FGFR1 is sufficient to provide resistance to T-DM1 we constructed HME2 and BT474 cells to specifically overexpress FGFR1 in the absence of other EMT-associated factors ( Fig.…”

“…Herein, we demonstrate that FGFR1 can act as a major driver of tumor recurrence following onset of HER2 discordance and acquisition of resistance to T-DM1 and other ErbB-targeted therapies. Previous studies from our lab and others suggest that FGFR can act as an bypass mechanism to facilitate resistance to ErbB kinase inhibitors (17,18,20,38). Furthermore, FGFR signaling has also been identified as a mechanism of resistance to endocrine therapies in breast and prostate cancer (19,39).…”

“…FGFR1 can also undergo gene amplification and translocation, and elevated expression of FGFR1 is associated with decreased clinical outcomes of breast cancer patients (14) (15,16). Work from our lab and others suggest that upregulation of FGFRs and FGF ligands can serve as resistance mechanisms for tumor cells that were originally sensitive to ErbB and endocrine-targeted therapies (16)(17)(18)(19)(20). In addition to enhanced expression of the receptor, our recent studies demonstrate that the processes involved in EMT work en masse to support FGFR signaling through diminution of E-cadherin and enhanced interaction with integrins (21).…”

Effects of FGFR1 Gene Polymorphisms on the Risk of Breast Cancer and FGFR1 Protein Expression

“…This co-amplification has also been associated with resistance to estrogen deprivation in ER+ breast cancer and poor patient outcome. Interestingly, Hanker et al found a copy number gains of FGF3/4/19 gene and evidence of increased FGFR signaling in HER2-amplified cell lines [27]. Preclinical and clinical evidence indicated that ER+ tumors with HER2 amplification responded poorly to endocrine therapy, particularly tamoxifen, probably due to the crosstalk between ER and HER2 signaling pathways [28,29].…”

miR‐511 inhibits proliferation and metastasis of breast cancer cells by targeting FGF4

“…For example, it enhances tumorigenesis and facilitates stem cell‐like properties in ovarian cancer by acting on the receptor FGFR2 . In breast cancer, FGF4 increases tumor growth rate, metastases, blood flow and oxygenation, and also possibly contributes to the resistance to lapatinib and trastuzumab of cancer cells . However, the mechanism of FGF4 dysregulation in breast cancer deserves further investigation.…”