Résumé
Most of targeted cancer drugs are developed in the clinical setting as single agent or as add-on of a standard treatment. Indeed, scarce data are available about the interaction effect in terms of synergism or antagonism for combinations of targeted agents or of targeted and cytotoxic agents at different doses. We studied the interaction effects of combinations of BKM120, MEK162 and SN38 (the active metabolite of irinotecan) on CRC cell lines.
A combination drug screening was performed on 7 CRC cell lines, 2 of which previously made resistant to irinotecan. For each cell line the combinations of BKM120 and MEK162, of BKM120 and SN38, and of MEK162 and SN38 were tested. Cell survival was assessed by sulforhodamine B cytotoxic assay in matrices of full-range dose combinations for both drugs. We developed an R script to perform a synergy analysis according to a modified version of the method proposed by Léhar and al. (Nat Biotechnol 2009;27:659-666). This method of analysis allows quantification of synergism or antagonism for each dose combination point in dose matrices of two or more drugs, and yields a synthetic interaction parameter, the combination index (CI). A CI of > 0 indicating synergy, a CI of < 0 antagonism, and a CI of 0 additivity.
We could detect a pronounced synergism between BKM120 and MEK162, with a mean combination index of 1.82 for the 7 cell lines tested. Drug combinations including chemotherapy showed less positive interactions. A moderate synergistic interaction was detected between SN38 and MEK162, with a mean CI of 1.16. Combinations of SN38 and BKM120 were mainly additive, with a mean CI of 0.17. Interestingly, the distribution of synergistic effect was not homogeneous over the dose matrices. Analysis of matrices for the BKM120/MEK162 combination showed focal areas with high synergy, which were quite always located in dose regions corresponding to IC10-IC30 for BKM120 and IC20-IC35 for MEK162. On the contrary, analysis of matrices for the BKM/SN38 combination showed focal areas of intense antagonism located in dose regions corresponding to IC15-IC30 for BKM120 and IC5-IC30 for SN38. No clear correlation was detected between, on the one side, the type of pharmacological interaction for all drug combinations tested and, on the other side, the mutational status of KRAS and p53, or sensitivity to irinotecan.
Our data show the importance of an extensive preclinical testing of the interaction effects of drug combinations at different doses. We are now performing synergism analysis of three dimension matrices for three-drug combinations. Phosphoproteomic analysis of drug combination effect on this high synergism areas compared to other dose matrix areas is ongoing, with the aim of elucidating the underlying molecular mechanism(s).
Citation Format: Diego Tosi, Salima Atis, Caroline Mollevi, Pierre Martineau, Céline Gongora. Synergism analysis of dose matrices for combinations of BKM120 (a PI3K inhibitor), MEK162 (a MEK1/2 inhibitor) and chemotherapy in colorectal cancer (CRC) cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3681. doi:10.1158/1538-7445.AM2014-3681