P1-12-06: The Role of MAPK and PI3K/AKT/mTOR Signaling in Innate Lapatinib Resistance.

Abstract Background: Lapatinib is a tyrosine kinase inhibitor which blocks downstream MAPK and P13K/AKT/mTOR proliferation and survival signaling pathways in HER2 positive breast cancer cell lines, tumor xenografts and HER2 positive breast cancer patients. However, pre-clinical and clinical studies have shown that not all HER2 positive patients respond to lapatinib and thus innate resistance to lapatinib exists. The identification of biomarkers of lapatinib response is therefore critical and would enable individual therapeutic decisions to be based on tumor biology rather than basic histopathology data alone. The aim of this study was to examine the role of MAPK and PI3K/AKT/mTOR signaling in a panel of lapatinib sensitive and resistant HER2−amplified breast cancer cell lines to identify pharmacodynamic markers of response to lapatinib treatment. Methods: Dose response curves were generated to determine sensitivity to lapatinib in a panel of 17 HER2−amplified breast cancer cell lines. Total and phosphorylated levels of HER2, HER3, EGFR, AKT, ERK, S6K and eEF2 were determined following 24 hours lapatinib treatment in each of the cell lines. Results: Twelve of the cell lines were sensitive to lapatinib with IC50g < 1 μM while 5 of the cell lines were innately resistant to lapatinib with IC50g > 1 μM. Levels of pHER2 and pHER3 were decreased in response to lapatinib in all cell lines independent of sensitivity to lapatinib. This suggests that inhibition of HER2/HER3 activation is not indicative of response to lapatinib treatment. There was also no correlation between the levels of HER2, HER3, and EGFR and sensitivity to lapatinib in the cell line panel. In lapatinib sensitive cell lines, lapatinib decreased PI3K (pAKT), mTOR (pS6K) and MAPK (pERK) signaling and increased peEF2 levels. In contrast the levels of pAKT, pS6K, peEF2 and pERK were maintained following lapatinib treatment in lapatinib resistant cells. The continued activation of these proteins in the presence of lapatinib suggests a possible feedback mechanism that warrants further investigation. These data confirm that maintained signaling through either the P13K/AKT/mTOR pathway or the MAPK pathways in the presence of lapatinib can be an early pharmacodynamic biomarker of response. Conclusions: Maintenance of pAKT, pS6K, peEF2 and pERK levels, in response to lapatinib treatment correlates with lapatinib resistance. These data suggest that alterations in the P13K/AKT/mTOR and MAPK pathways play an important role in innate lapatinib resistance and pharmacologically targeting these pathways is a rational therapeutic approach for overcoming innate lapatinib resistance. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-06.