Fig. 5
ABn treatment reduces viability of MYC-high triple-negative breast cancer cell lines, inhibits tumor growth, and extends survival in patient-derived xenografts. a A summary of the results of BH3 mimetic screen in MCF10A MycER cells. The numbers refer to fold change as in Supplementary Figure 4A. The drugs were navitoclax, venetoclax, a BCL-XL-selective inhibitor A-1155463 and an MCL-1-selective inhibitor A-1210477. b AB treatment-induces apoptosis in MYC-high PDEc. The cultures were treated with DMSO, 1 μM navitoclax, 10 mM metformin or combination for 24 h. Blinded scoring of apoptosis was carried out for all samples. c MYC expression in 17 triple-negative breast cancer cell lines. MYC index: MYC intensity normalized to a blot-to-blot reference sample, highest intensity band (HCC1599) and loading control. N.B. HCC1599 excluded from the final analysis due to poor growth. Tubulin: Loading control. d The effect of AB treatment on the viability of MYC-low and MYC-high TNBC cell lines. The upper panel shows kill curves and the dashed line marks the EC20 of navitoclax (20% reduction in survival); see also Fig.S4E. The lower panel shows metformin effect at EC20 of navitoclax. Student’s t-test (unpaired), SD. e Summary table of drug treatments in TNBC cell lines. The cell lines were categorized according to MYC index (0 = undetectable MYC expression; + to +++ = relative MYC expression level). Blue boxes indicate statistically non-significant and pink boxes statistically significant differences between each single-agent treatment and the corresponding combination. Student’s t-test (unpaired). f Representative images of tumors developing in TNBC-PDX mice. Black arrows: Primary tumors developing at the site of the tumor grafts; blue arrows: Metastases. g TNBC-PDX tumors retain MYC expression during in vivo passaging. Tumor generations G1–G3. h Effect of AB treatment on tumor growth and survival in cohorts of TNBC-PDX mice. The mice were treated with vehicle, 100 mg/kg/d navitoclax, 600 mg/kg/d metformin or the combination for 21 days, and followed up until day 60. Student’s t-test (unpaired), SEM. In the survival graph: P-value: Significant difference between vehicle and AB-treated cohorts
