A synergistic interaction between lapatinib and topoisomerase I inhibitors in cisplatin sensitive and resistant cancer cell lines

Abstract

14618 Background: Lapatinib is a HER1 and 2 tyrosine kinase inhibitor (TKI). Little is know about its interaction with other chemotherpy drugs. In this work investigate interactions between lapatinib and cisplatin or SN-38 (the active metabolite of irinotecan) in cisplatin sensitive (testis cancer) and resistant cancer cell lines. Methods: We obtained 3 cancer cells lines (833K, GCT27, SUSA) all of which had cisplatin resistant daughter lines (833Kr, GCT27r, SUSAr). These resistant lines were established by exposing the sensitive lines to increasing doses of cisplatin. Western Blot analysis was used to estimate HER 1–4 levels and expression of proteins in the PI3K and MAPK pathways. The IC 50s for lapatinib, cisplatin and SN-38 were calculated in these cell lines. These drugs were then given in combination, and the effect was estimated using calcusin plots. Flow cytomery was used to estimate the effect on the cell cycle and apoptosis. Identical experiments were carried out with Pazopanib, instead of lapatinib, which was used as a control. Results: The IC50 for lapatinib in the resistant and sensitive cell lines were similar (4.0–5.0 micromolar and 3.6–4.4 micromolar respectively). Sensitivity was not related to HER 1–4 expression. Synergistic interactions were observed between SN-38 and lapatinib in all 6 cell lines (calculated combination indices <0.7 in all lines). No synergistic interaction was seen between cisplatin and lapatinib. Cell cycle data revealed the synergistic combination was associated with an increase in apoptosis and reduces cell cycle arrest. Pazopanib was not associated with a synergistic interaction in any of the cell lines with either cisplatin or SN-38. Conclusions: Lapatinib appears equally efficacous in both cisplatin sensitive and resistant cell lines. A synergistic interaction occurs between lapatinib and SN-38 in this model which is associated with increased apoptosis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GlaxoSmithKline