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. 2014 Mar 28;24(5):542–559. doi: 10.1038/cr.2014.37

Figure 3.

Figure 3

Sequential application of Ab7.16.4 + BEZ235 combination overcomes Ab7.16.4 + lapatinib resistance. (A) WST-1 proliferation assay after 72 h of treatment with different drugs targeting PI3K and/or mTOR. Primary cells (129F.A + L.R and 134F.A + L.R) from PTEN−/−/NIC mice treated with Ab + lapatinib over 4 weeks were used. ***P < 0.001, by one-way ANOVA and ***P < 0.001, by two-tailed t-test. (B) Western blot analysis of primary cells treated with the indicated drugs for 3 h. (C) Tumor volume measurements at different time points for transplant mice (782_L and 782_R) treated with Ab + lapatinib first and then with Ab + BEZ235 on day 12 upon resistance development. (D) Tumor volume fold change of transplant mice treated with vehicle (ctrl) or Ab7.16.4 + lapatinib or A + L/A + B. *P < 0.05, by two-tailed t-test. (E) Upper panel, WST-1 proliferation assay after 72 h treatment with the indicated drugs targeting PI3K and/or mTOR pathways in BT474.LapR cells. ***P < 0.001, by two-tailed t-test. Lower panel, western blot analysis of signaling pathways in BT474.LapR cells upon treatment with different drugs or their combination for 3 h. (F) Survival analysis of the PTEN−/−/NIC mice treated with vehicle (ctrl) or Ab + lapatinib or A + L/A + B. The switch time for treatment was shown with a green arrow on the x-axis for the sequential therapy-treated mice. P-value was determined by log-rank test. P = 0.0001 is between Ab7.16.4 + lapatinib and A + L/A + B sequential therapy.