Figure 8. Pharmacological inhibition of the SFKs potentiates the antitumor effect of BKM120 and fulvestrant in vivo.

(A) MCF-7 cells stably transduced with GFP, LYN^WT, or LYN^D189Y were treated with 10% DCC-FBS with or without 1 μM dasatinib, 1 μM BKM120, or 1 μM fulvestrant. Media and drugs were replenished every 3 days. Cells were counted after 5 days. Data are presented as percentage of control (n = 3; *P < 0.0001 vs. respective Con, ^#P < 0.01 vs. Fulv). (B) MCF-7 cells were injected s.c. into athymic ovariectomized mice supplemented with short-term 14-day release 17β-estradiol pellets. Mice bearing tumors ≥150 mm³ were randomized to vehicle, dasatinib (15 mg/kg/d, p.o.), BKM120 (30 mg/kg/d, p.o.) and fulvestrant (5 mg/wk, s.c.), or BKM120, fulvestrant, and dasatinib for 7 weeks. Data are presented as log₂ of mean tumor volume (*P < 0.0001 vs. vehicle, ^#P < 0.01 vs. BKM and Fulv or dasatinib). (C) Xenografts from B were homogenized 4 hours after the last dose of BKM120 or dasatinib and 24 hours after the last dose of fulvestrant. Tumor lysates were analyzed by immunoblot using the indicated antibodies. (D) IHC for Y416 P-SRC. Representative images of tumors from A and quantitative comparison of membrane histoscores, as described in the Methods (H-score; *P < 0.0001). Scale bars: 200 μm.