Resistance to a combination of human epidermal growth factor receptor 2 (HER2)-targeted therapies, trastuzumab and lapatinib, was associated with elevated activation of a group of proteins called fibroblast growth factor receptors (FGFRs), which are the target of a number of drugs currently being developed. These preclinical results were presented at the American Association for Cancer Research 2014 Annual Meeting, in San Diego, California.

About 20% of breast cancers have elevated levels of the protein HER2 and are considered HER2-positive. Drugs that target HER2 have improved outcomes for patients with HER2-positive breast cancer, but most tumors eventually become resistant to the effects of these drugs.

“A number of clinical trials have shown that treatment with a combination of two HER2-targeted therapies is superior to treatment with either alone,” said Joan T. Garrett, PhD, research instructor at Vanderbilt University Medical Center in Nashville, Tennessee. “However, resistance to this dual blockade of HER2 eventually arises.

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“The goal of this study was to identify how HER2-positive tumors develop resistance to dual blockade of HER2 with trastuzumab and lapatinib,” she continued. “Our finding that amplification of FGF3, 4, and 19 is associated with resistance to this drug combination is significant because it opens up an avenue of research that could provide the basis for clinical testing of FGFR inhibitors, if all the results are consistent with what we have seen so far.”

Garrett and colleagues started the study by treating mice bearing tumors comprising a human HER2-positive breast cancer cell line with trastuzumab and lapatinib. The tumors disappeared and treatment was stopped. In some mice, however, the tumors recurred and would not respond to further treatment with trastuzumab and lapatinib. More than 90% of these tumors also failed to respond to a second combination of HER2-targeted therapies, trastuzumab and pertuzumab.

One approach the researchers used to understand the molecular mechanisms of resistance to trastuzumab and lapatinib was next-generation genome sequencing. Analysis of five tumors resistant to trastuzumab and lapatinib and five tumors sensitive to the drug combination showed that one of the resistant tumors had extra copies of the genes FGF3, FGF4, and FGF19.

According to Garrett, these genes produce proteins that attach to FGFRs, triggering cell growth. Garrett and colleagues found that tumor cells with extra copies of the genes FGF3, FGF4, and FGF19 showed signs of elevated FGFR activation, as measured by levels of phosphorylated FGFR.

“This suggests that amplification of FGFR signaling could be a mechanism of acquired resistance to dual blockade of HER2,” said Garrett. “We are in the early stages of experiments designed to test whether drugs that block FGFRs, FGFR inhibitors, are effective in mice whose tumors have become resistant to the combination of trastuzumab and lapatinib. 

“If we observe tumor shrinkage or elimination in this setting and can show that FGFR signaling is amplified in HER2-positive breast tumors from patients treated with dual blockade of HER2, we will have a good rationale for considering clinical trials,” she added.