Fig. 4
Validation of MCL1 as a druggable driver in BRCA1-mutated TNBC. a MAGeCK software was used to compute RRA scores for all genes included in our focused shRNA library, showing depletion of Mcl1 shRNAs in WB1P-Myc organoids. b Immunohistochemical detection of MCL1 in multiple independent WB1P and WB1P-Myc tumors. Bar, 400 µm. c Overview of the non-germline mouse models for mammary-specific Mcl1 overexpression. d Kaplan–Meier curves showing mammary tumor-specific survival for the different models. B1P and B1P-Myc females injected with Lenti-Mcl1P2ACre showed a reduced mammary tumor-specific survival compared to B1P and B1P-Myc female mice injected with Lenti-Cre, respectively (180 days after injection vs 238 days after injection; **P < 0.01 by Mantel-Cox test; 70 days after injection vs 126 days after injection; ****P < 0.0001 by Mantel-Cox test). e In vitro response of WB1P and WB1P-Myc organoids to MCL1 inhibitor S63845. Error bars represent standard error of the mean. Experiment was performed in triplicate. f In vivo response of organoid-derived WB1P and WB1P-Myc tumors to S63845, as visualized by Kaplan–Meier curves. WB1P and WB1P-Myc organoid lines were transplanted in the fourth mammary fat pad of nude mice. When tumors had reached a size of 100 mm3, mice were treated with 25 mg kg-1 S63845 (i.v. once-weekly for 5 weeks) or vehicle. g Response of the BRCA1-mutated TNBC PDX-110 xenograft model to S63845 and the PARP inhibitor olaparib, as visualized by tumor volume curves (left) and Kaplan–Meier curves (right). Single-cell suspensions of PDX-110 were transplanted in the fourth mammary fat pad of NOD-SCID-IL2Rγc–/– mice. When tumors had reached a size of 100 mm3, mice were treated with 25 mg kg−1 S63845 (i.v. once-weekly for 4 weeks), 50 mg kg−1 olaparib (i.p. 5 days out of 7 for 4 weeks), both drugs or vehicle. Combination therapy with S63845 and olaparib prolonged survival compared to olaparib monotherapy (****P < 0.0001 by Mantel-Cox test). Error bars represent standard error of the mean
