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Aberrant expression or activation of epidermal growth factor receptor (EGFR) family members contributes to radioresistance. We have previously shown that lapatinib, a dual EGFR/HER2 kinase inhibitor, inhibits proliferation and radiosensitizes EGFR overexpressing breast cancer cell lines in vitro. We hypothesized that lapatinib would radiosensitize EGFR and HER2 overexpressing breast cancer cells to ionizing radiation in vivo.
 Using an EGFR overexpressing breast cancer xenograft system, we show that lapatinib (100 mg twice daily) inhibits EGFR phosphorylation and decreases tumor volume by nearly 50% when combined with radiation, consistent with an enhancement ratio of 1.34 and a fractional tumor volume (FTV) ratio of 2.28. This data suggests a synergistic effect of radiation and lapatinib in this model and is consistent with results from in vitro systems previously reported. According to our predefined endpoint of tumor volume at 21 days, we saw no benefit from the addition of lapatinib to radiation in HER2 overexpressing xenografts (FTV ratio of 0.13). However, we did observe durable tumor control with the combination therapy (time to quadrupling of tumor volume: 102 days for radiation + lapatinib, 39 days for radiation, 31 days for lapatinib, and 12 days for control. In the HER2 overexpressing cell lines, inhibition of phospho-Akt was seen in all treatment groups, suggesting an important role for the PI3-K/Akt pathway in growth delay. Next, we developed several primary human tumor xenografts in which breast cancer patient biopsies were implanted into the gonadal fat pad of mice. Using gene expression analysis, we showed that the molecular subtype remained consistent following serial passage. Finally, we showed that, in our initial primary xenograft, there was no synergistic effect of radiation and lapatinib treatment on phospho-Akt, phospho-ERK, apoptosis, or proliferation. These results suggest that EGFR overexpressing breast cancers may be susceptible to radiosensitization by lapatinib and that primary tumor xenografts may aid in the testing of hypotheses from clinical/translational research.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA