Abstract
To determine whether the dual EGFR/HER2 kinase inhibitor lapatinib can radiosensitize EGFR+ breast cancer in vivo, mice bearing xenografts of basal‐like/EGFR+ SUM149 breast cancer cells were treated with lapatinib and fractionated radiation therapy over a 10 d period and tumor growth inhibition determined and correlated with changes in activation of downstream signaling to ERK1/2 and AKT by immunohistochemistry. Basal‐like/EGFR+ SUM149 breast cancer tumors were completely resistant to treatment with lapatinib alone but highly growth impaired with lapatinib + radiation exhibiting an enhancement ratio average of 2.75 and a fractional tumor product ratio average of 2.06 over the duration of the study. Immunohistochemical analysis demonstrated that radiosensitization by lapatinib correlated with inhibition of ERK1/2 but not AKT. In vitro analysis of other basal breast cancers consistently demonstrated a loss of radiation induced MEK1/2 inhibition with lapatinib treatment. Treatment of the SUM102 basal‐like/EGFR+ cell line with the MEK inhibitor CI1040 resulted in radiosensitization at levels similar to that seen with lapatinib alone. Furthermore, constitutive activation of RAF in SUM102 cells abolished the ability of lapatinib to radiosensitize these cells and resulted in enhanced radioresistance relative to parental cells. Collectively, this work demonstrates that lapatinib radiosensitizes EGFR+/basal‐like breast cancer both in vitro and in vivo in a MEK/ERK dependent manner, and suggests that lapatinib in combination with fractionated radiation therapy may provide an effective treatment option for breast cancers of this subtype.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B73.
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