Skip to main content
. Author manuscript; available in PMC: 2018 Apr 27.
Published in final edited form as: Sci Transl Med. 2017 May 31;9(392):eaal5148. doi: 10.1126/scitranslmed.aal5148

Figure 2. Mutant KRAS mediates resistance to PARP inhibitors and sensitivity to the PARP and MEK inhibitors.

Figure 2

(A) Drug response curves for BMN673 combined with AZD6244 in 24 well-characterized ovarian cancer cell lines treated with varying concentrations of the two compounds for 96 hr. CI was calculated using CalcuSyn software with the Chou-Talalay equation. CI values reflect the sign and magnitude of drug-drug interaction: < 0.5 synergy, 0.5–1 additivity, and >1 antagonism. Red cell line name: synergy (CI < 0.5); blue cell line name: cells intrinsically sensitive to PARPi; black cell line name: cells exhibited modest to no response to either mono or combination treatment.

(B) Upper panel: Percentage cell growth inhibition at 10 µM BMN673 from Figure 2A, Lower panel: Selected mutations in cell lines. KRAS and BRCA2 correlations with BMN673 response were significant (p=4.7×10−5 and p=0.023, respectively).

(C) Upper panel: Percentage of cell growth inhibition by AZD6244 from Figure 2A. Lower panel: Selected mutations in cell lines. KRAS correlation with AZD6244 response was significant (p =0.026).

(D) Correlation between IC50 of BMN673 and AZD6244 (Pearson’s r = − 0.412, p=0.049).

(E) Upper panel: CI values, cells were arranged by CI into synergistic (green) and non-synergistic (red) (cutoff = 0.5) based on Figure 2A. Lower panel: Selected mutations in cell lines. KRAS mutation is correlated with synergistic effect between PARPi and MEKi (p =3×10−6).

(F) Interactions between BMN673 and AZD6244 (MEKi), GSK1120212B (MEKi), SCH772984 (ERKi), GSK2118436A (BRAFi), SP600125 (JNK inhibitor), PD0332991 (CDK4/6 inhibitor), and BKM20 (PI3Ki) were examined across a panel 10 cell lines including 8 RAS mutant lines and 2 RAS wild type lines (cell line data in fig. S3A, 3B).

(G) Response of Ba/F3 cells rendered IL3-independent with KRAS_WT, KRASG12D, KRASG12V, or PIK3CAH1047R to BMN673 and AZD6244/SCH772984.

(H) Heatmap of CI of combinations of BMN673 with AZD6244 and SCH772984 from 2G. Combinations with BMN673 and GSK2118436A (BRAFi) and SP600125 (JNK inhibitor) are also presented.