Abstract B058: Drug resistant HER2Δ16 overexpression cells are sensitive to a new class of tyrosine kinase inhibitors
Authors: Sfondouris Mary E. , Sridhar Jayalakshmi , Stevens Cheryl , Jones Frank 
Published: May 2015

HER2 positive breast tumors make up 15-20% of reported breast cancer cases and are associated with poor prognosis and increased mortality due to enhanced rates of metastatic disease. Trastuzumab is commonly used to treat HER2 positive tumors, however, when used alone 76-88% of patients showed de novo resistance to the drug while patients sensitive to trastuzumab go on to develop resistance. When used with chemotherapy, patients experience improved benefit, but nearly half of these patients will still experience metastatic disease progression. The difference in treatment success may be due to the variable genotypes of individual tumors. One such variant is the unique tumor specific isoform of HER2, HER2Δ16, which promotes tumorigenic phenotypes and trastuzumab resistance. Indeed, we have shown that 90% of metastatic HER2 positive breast cancers tested also express HER2Δ16. Since HER2Δ16 overexpression leads to resistance to trastuzumab, directly targeting the kinase activity of HER2Δ16 could potentially slow growth of cancer cells expressing this isoform. Here we show that HER2Δ16 overexpression also promotes resistance to the dual HER2/EGFR kinase inhibitor, lapatinib, currently in clinical use for the treatment of patients that fail trastuzumab. Therefore, our goal is to find small molecules that can act to inhibit HER2Δ16, thereby reversing resistance to current therapies. The HER2 kinase inhibitor Emodin (1,3,8-trihydroxy-6-methyl-anthraquinone) also inhibits HER2Δ16 activation, and as such, been used as the base structure for developing more effective inhibitors. Emodin binds the hinge region in the ATP binding pocket of the kinase domain, therefore molecules with similar structures may also act as HER2Δ16 inhibitors. We tested 13 small molecules that are structurally similar to emodin on MCF-7 breast cancer cell lines that express HER2, HER2Δ16 or empty vector. Of the 13, we found three molecules that suppressed cell viability potently in all three cell lines at 10μM. HER2 and EGFR phosphorylation were suppressed in these cell lines after exposure to each of the drugs, similar to lapatinib. Finally, we measured the IC50 of each drug and found that the two most effective drugs also had similar IC50 concentrations for both the HER2 and HER2Δ16 overexpression cell lines. With IC50 values of &lt;1μM for HER2Δ16 cells, these two drugs are also more effective at inducing cell death compared to lapatinib with an IC50 &gt;10μM. These results indicate the potential of either of these drugs to effectively inhibit HER2Δ16 and thus combat the drug resistance seen in HER2Δ16 expressing tumors.

Citation Format: Mary E. Sfondouris, Jayalakshmi Sridhar, Cheryl Stevens, Frank Jones. Drug resistant HER2Δ16 overexpression cells are sensitive to a new class of tyrosine kinase inhibitors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr B058.