Fig. 2: STING agonism potentiates the therapeutic efficacy of PARP inhibition in a BRCA-deficient model of TNBC, overcomes resistance and contributes to immunologic memory.
Tumor chunks from the K14-Cre-Brca1f/f;Trp53f/f GEMM were transplanted in syngeneic FVB/129P mice, which were treated with vehicle, olaparib (daily), ADU-S100 (weekly) or their combination (6–8 mice/group). Tumor volume was measured twice weekly and survival recorded. a Tumor volumes in individual mice over time. b Log2 fold-change in tumor volumes at weeks 1, 4, 8, 12. P values were determined using one-way ANOVA with Holm-Sidak post-hoc test at weeks 1 and 4 and with unpaired t-tests with Welch’s correction at weeks 8 and 12. c Percent survival. Median survival shown in brackets. Statistical analysis was performed using the Log-rank (Mantel–Cox) test. Intratumoral ADU-S100 injections were stopped when the tumor was cleared. d Weight of mice treated with vehicle, olaparib, ADU-S100 or their combination. e Murine KB1P-G3 CRISPR/Cas9 control or STING knockout (STING KO) cells were treated with vehicle (-, 0), 1 μM olaparib, the indicated doses of ADU-S100 (μg/ml) or their combination for 72 h and subjected to immunoblotting. f KB1P-G3 CRISPR/Cas9 control or STING KO tumors were transplanted in syngeneic FVB/129P2 mice, which were treated with vehicle, olaparib (daily), ADU-S100 (weekly) or their combination (4–8 mice/group). Tumor volumes (mm3) were measured twice weekly. Statistical analysis was performed using one-way ANOVA with Holm-Sidak post-hoc test. (Inset) Immunoblotting for total STING protein levels in KB1P-G3 control or STING KO tumors. g Tumor chunks were implanted in naïve mice or in the opposite mammary fat pads of those previously cured by combined olaparib/ADU-S100. Tumors could not be re-established in the latter mice.
