Abstract
14643 Background: Inhibition of members of the HER-family remains an important therapeutic strategy in multiple malignancies. Lapatinib (Tykerb) is a dual EGFR HER-2-targeted tyrosine kinase inhibitor currently approved in combination with the oral 5-fluorouracil (5-FU) pro-drug capecitabine for the treatment of breast cancer patients who have previously failed multiple therapies. To better understand the mechanistic basis for lapatinib combination therapy, this study investigated the interaction between Lapatinib and 5-FU and irinotecan in two colon (HT-29 and LoVo) and two gastric (AGS and MKN-28) cell line models with varying EGFR and HER-2 levels. Methods: EGFR and HER-2 expression levels were determined by Western blotting. Response of colon and gastric cell lines to treatment with Lapatinib, 5-FU and SN-38 (irinotecan active metabolite) was evaluated by MTT growth inhibition and cell survival assays. Drug combinations were evaluated by combination indices using the methods of Chou-Talalay. Flow cytometric analysis was employed to analyze cell cycle effects and induction of apoptosis in selected drug combinations. DNA damage was quantified by detection of H2A.X phosphorylation in response to DNA double strand breaks. Results: Lapatinib in combination with either 5-FU or SN-38 resulted in synergistic growth inhibition in all gastric and colon cell line models tested with varying EGFR and HER-2 status. Furthermore, the triple combination of Lapatinib, SN-38 and 5-FU resulted in highly synergistic growth inhibition. In addition, Lapatinib in combination with SN-38 demonstrated highly synergistic suppression of clonogenic cell survival. Flow cytometric analysis demonstrated that the addition of Lapatinib to SN-38 dramatically enhanced cell cycle arrest at the G2/M checkpoint, rapidly activated caspase-8, and potently induced apoptotic cell death. Analysis of H2A.X indicated that Lapatinib enhanced the generation of SN-38-induced DNA double-strand breaks. Conclusions: These data provide compelling preclinical rationale supporting the inclusion of Lapatinib in gastrointestinal chemotherapeutic regimens containing irinotecan and 5-FU. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology GlaxoSmithKline, Pfizer Oncology
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