Differential Sensitivity of ERBB2 Kinase Domain Mutations towards Lapatinib

摘要: Background Overexpression of the ERBB2 kinase is observed in about one-third breast cancer patients and dual ERBB1/ERBB2 inhibitor lapatinib was recently approved for treatment advanced ERBB2-positive cancer. Mutations receptor have been reported at diagnosis also gastric, colorectal lung These mutations may an impact on clinical responses achieved with a potential use other solid cancers. However, sensitivity towards clinically not known. Methodology/Principal Findings We cloned panel 8 mutations, established stable cell lines characterized their alternative inhibitors. Both lapatinib-sensitive lapatinib-resistant were observed. Interestingly, we able to generate resistance wt-ERBB2 cells incubated prolonged periods time. This indicates that these cause secondary lapatinib-treated patients. Lapatinib-resistant found be highly resistant AEE788 but remained sensitive irreversible inhibitors CL-387785 WZ-4002. Conclusions/Significance Patients harbouring certain domain benefit from treatment. Moreover, develop due mutations. Irreversible offer options tumor In addition, interest scenario resistance.