Article Figures & Data
Figures
- Figure 1.
BMN 673 potently inhibits growth of SCLC in vitro. Proliferation assays using BMN 673 showed SCLC to be exquisitely sensitive to BMN 673 (A). Interestingly the IC50 values of SCLC to BMN 673 and cisplatin indicated a moderate correlation (B).
- Figure 2.
BMN 673 inhibits SCLC growth in vivo. Animals bearing NCI-H209 and NCI-H1048 flank xenografts treated with BMN 673 showed delayed tumor growth without significant toxicity (A). Lysates prepared from xenografts harvested 2 hours after treatment on day 3 showed decreased poly-ADP ribose (PAR) levels (B) indicating strong inhibition of PARP activity in vivo by BMN 673. (Data presented as mean ± SEM, *P < 0.05, ***P < 0.01).
- Figure 3.
SCLC IC50 to BMN 673 is inversely correlated to DNA repair protein expression. IC50 to BMN correlated to expression of DNA repair proteins (A) demonstrates a strong inverse correlation, as cell lines with higher expression of DNA repair proteins by RPPA are more sensitive to PARP inhibition. DNA repair cluster within the correlation matrix, made up of a group of DNA repair proteins whose expression is highly correlated (B). The correlation to DNA repair is also observed when the “DNA repair score” is applied to the RPPA dataset (C). Proposed model of PARP inhibitor activity in SCLC (D).
- Figure 4.
PI3K pathway activity correlates to PARP inhibitor resistance. SCLC cell lines with more active PI3K signaling are less sensitive to BMN 673 (A). Similarly, higher pAkt correlates to decreased sensitivity to cisplatin (B).
Tables
- Table 1.
SCLC cell lines: mutational status and IC50 values
Cell line TP53 RB1 MYC amp. BMN 673 IC50 (nmol/L) Cisplatin IC50 (nmol/L) H209a mt mt None 1.7 45.5 H1048 mt mt None 2.2 1,087 H524a mt mt MYC 3.1 976 H1930a mt wt None 4.1 153 H69a mt mt MYCN 5.2 2,723 H2081 wt mt None 6.3 2,669 H2107a mt mt MYCL1 7.3 811 H1092a mt wt MYCL1 8.9 1,611 DMS-79a mt mt None 9.3 1,189 H446a mt mt MYC 13 2,074 COR-L279 mt mt Unk 15 620 NOTE: BMN 673 and cisplatin IC50 values calculated from proliferation assays. Mutational status of SCLC cell lines tested for TP53, RB1, and MYC amplification (mt, mutant; wt, wild type; Unk, unknown) are shown.
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↵aProtein profile included in proteomic analysis.
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Supplementary Data
Files in this Data Supplement:
- Supplementary Figure 1 - PDF file - 233K, Plots correlating protein expression for components of the DNA Repair Score not shown in Figure 3.
Volume 19, Issue 22
