Figure 7.
Early treatment with CDK4/6 plus PI3K inhibitors prevents acquisition of resistance in PDXs, but is not efficacious in resistant cells. A, relative growth of parental (MCF-7 and T47D) and palbociclib-resistant (MCF-7pR and T47DpR) cell lines treated for 6 days with control vehicle, 500 nmol/L palbociclib, 250 nmol/L GDC0941 (0941), or the combination (*, P < 0.05; ***, P < 0.001; NS, not significant, two-way ANOVA with Tukey multiple comparisons test). B, clonogenic survival assays in MCF-7pR and T47DpR cells treated for 14 days. C, BrdUrd incorporation-ELISA assays in cells treated for 24 or 72 hours (*, P < 0.05 palbociclib or GDC0941 vs. combination at 72 hours, two-way ANOVA with Tukey multiple comparisons test). D, Western blots of resistant cells treated for 96 hours as indicated. E, relative tumor growth of PDX244 following vehicle, BYL719, LEE011, or the combination (***, P < 0.0003 Student t test for LEE011 vs. BYL719 plus LEE011). F, Western blot analysis with the indicated antibodies in PDX244 after 103 days of vehicle, BYL719, LEE011, or the combination. Each lane belongs to one individual tumor.