Confirmation of synergy and cytotoxicity of genotype-selective drug pairs. Confirmation of synergy and cytotoxicity of genotype-selective drug pairs. A,

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Confirmation of synergy and cytotoxicity of genotype-selective drug pairs. Confirmation of synergy and cytotoxicity of genotype-selective drug pairs. A, formal assessment of synergy of lapatinib or bosutinib with MK-2206, and simvastatin with flavopiridol or 17-DMAG on representative BRAF mutant and RAS mutant melanomas, by Chou–Talalay isobologram analysis. Data are normalized, with connecting line at X and Y = 1 corresponding to the line of additivity. Datapoints falling below line are synergistic, along or near the line are additive, and above the line are antagonistic (see key). Data represent averages for 3 separate experiments. Combination indices and growth inhibition values can be found in Supplementary Table S9. B, flow cytometry of Annexin-V and propidium iodide viability markers after lapatinib (2.5 μmol/L) and MK-2206 (5.0 μmol/L) treatment alone or in combination, or simvastatin (2.5 μmol/L) and flavopiridol (0.1 μmol/L) alone or in combination with representative lines YUMAC (BRAF mutant) or YUGASP (NRAS mutant). Numbers in the lower right quadrant correspond to early apoptotic cells, whereas numbers in the top right and left quadrants correspond to late apoptotic and necrotic cells, respectively. Flow cytometry for vehicle-only controls and other combinations are shown in Supplementary Fig. S3F. C, percent viability for combinations tested by flow cytometry, as in B. N = 3 for all experiments. Error bars, mean ± SD. P values calculated by Student t test; *, P < 0.05. D, evaluation of drug-class effects. Representative concentration–response curves of single agents or dual-agent combinations showing enhanced growth inhibition in mutant BRAF cells, using the EGFR inhibitor gefitinib with MK-2206 (top row) or atorvastatin with flavopiridol in mutant RAS cells (bottom row) in relation to the predicted Bliss independence model. See also Supplementary Fig. S4. For statin combinations with flavopiridol, top and bottom x-axes represent concentrations used for each drug with those same concentrations used in combinations. Same-concentration combinations were used for gefitinib and MK-2206. Matthew A. Held et al. Cancer Discovery 2013;3:52-67 ©2013 by American Association for Cancer Research