Mechanisms of resistance to lapatinib in HER2 positive breast cancer

摘要: Lapatinib is a tyrosine kinase inhibitor of HER2 which blocks downstream signaling pathways in positive breast cancer cell lines, tumor xenografts and patients. However, pre-clinical clinical studies have shown that patients can exhibit either innate or acquired lapatinib resistance. Previous work our laboratory resulted the generation lapatinib-resistant SKBR3 cells decreased phosphorylation eEF2 compared to parental cells. The aims this study were develop additional models resistance, characterise lines identify validate alterations may contribute resistance. HCC1954-L are novel line model developed through low-dose continuous conditioning with lapatinib. Using array CGH technology, HCC1954-L found increased amplification expression STARD3. SKBR3-L was be regulated by Ser359 eEF2k an mTOR-independent manner, suggesting role for SILAC-proteomic analysis SKBR3-par identified number different proteins CDK1, GAPDH, HER2, SELENBP1, SET EBP1 validated. HCC1419 revealed potential mechanism action – induction senescent-like phenotype, reversed when removed from media, possible dependent on p53 p16 expression. Alterations AKT, ERK, p70S6k correlated sensitivity panel ~HER2-amplifed lines. In conclusion, data suggests several mechanisms resistance warrant further investigation vivo ultimately