Fig. 7: PI3K inhibition sensitizes non-basal-like BC PDX to CDK4/6i.

A Waterfall plot showing the growth of n = 23 PDX treated with ribociclib 75 mg/kg plus alpelisib 35 mg/kg (bars and black dots) and vehicle (white circles). The percentage change from the initial volume is shown at day 35 of treatment. Dashed lines indicate the range of PD (>20%), SD (20% to −30%) and PR/CR (<−30%). The number of tumors treated per model is indicated in the brackets (n). Hashtags (#) indicate models harboring mutations in PIK3CA. Data represent mean values and error bars ± SEM. Boxes underneath show the molecular and intrinsic tumor subtype as well as their responses to the indicated treatments. The preclinical benefit to each drug is indicated as percentage in brackets. n.d, not determined. B IHC analysis of KI67 (left graph; p-value < 0.001) and phospho-pRb S807/811 (right graph; p-value < 0.01) in vehicle and alpelisib plus ribociclib-treated PDXs according to the PDX response to alpelisib plus ribociclib. Data are presented as mean values of each PDX. Two-tailed p-values are based on Mann-Whitney U test for all biological replicates. Different colors represent the tumor’s intrinsic subtype. R, resistant; S, sensitive; Alp, alpelisib; Rib, ribociclib. C Relative tumor growth of PDX039 and PDX191 after treatment with the indicated drugs and time. Dashed lines indicate the range of PD (>1.2), SD (1.2 to −0.7) and PR/CR (<−0.7). Two-tailed p-values are based on the two-way ANOVA test with Bonferroni’s method correction. V, vehicle; R, ribociclib; A, alpelisib. D, E Relative tumor growth of the ribociclib-resistant PDX244LR#18R and PDX450 after treatment with the indicated drug(s) for the indicated period of time, respectively. Dashed lines indicate the range of PD (>1.2), SD (1.2 to −0.7) and PR/CR (<−0.7). F Immunoblot of the indicated proteins in PDC476.2 treated with vehicle or 500 nM palbociclib as single-agent or combined with 100 nM fulvestrant and/or 2.5 µM alpelisib in ex vivo cultures for 48 h. At least two independent experiments were conducted. Source data are provided as a Source Data file.