Abstract
We analyzed survival effects for 15 different pairs of clinically relevant anti-cancer drugs in three iso-genic pairs of human colorectal cancer carcinoma cell lines, by applying for the first time our novel software (R package) called COMBIA. In our experiments iso-genic pairs of cell lines were used, differing only with respect to a single clinically important KRAS or BRAF mutation. Frequently, concentration dependent but mutation independent joint Bliss and Loewe synergy/antagonism was found statistically significant. Four combinations were found synergistic/antagonistic specifically to the parental (harboring KRAS or BRAF mutation) cell line of the corresponding iso-genic cell lines pair.COMBIA offers considerable improvements over established software for synergy analysis such as MacSynergy™ II as it includes both Bliss (independence) and Loewe (additivity) analyses, together with a tailored non-parametric statistical analysis employing heteroscedasticity, controlled resampling, and global (omnibus) testing.In many cases Loewe analyses found significant synergistic as well as antagonistic effects in a cell line at different concentrations of a tested drug combination. By contrast, Bliss analysis found only one type of significant effect per cell line.In conclusion, the integrated Bliss and Loewe interaction analysis based on non-parametric statistics may provide more robust interaction analyses and reveal complex patterns of synergy and antagonism.
Highlights
New targeted cancer drugs designed to interfere with specific signal transduction pathways [1] provide oncologists with new tools for cancer treatment but progress in anti-cancer pharmacotherapy is still very limited in terms of long time survival [2, 3]
Analyses were performed to identify synergism/ antagonism suggested by joint Bliss and Loewe analyses as presented in first subsection for all the drug pairs and cell lines studied, followed by a summary (Table 1) pinpointing the interactions found to be nonspecific second subsection or specific third subsection to KRAS/BRAF mutations
A combination is said to be specific if it exhibit synergy/antagonism only in the parental cell line of an iso-genic pair
Summary
New targeted cancer drugs designed to interfere with specific signal transduction pathways [1] provide oncologists with new tools for cancer treatment but progress in anti-cancer pharmacotherapy is still very limited in terms of long time survival [2, 3]. Most cancer drug treatments in use are combination regiments developed by adding compounds with novel mechanisms of action to drug treatments in use This current selection of anti-cancer drug combinations for use in the clinic is mostly based on conceptually simple theoretical models of the underlying biochemical processes involved assuming synergistic or at least additive anti-tumour effects will emerge when combining established cancer drugs [2]. As illustrated by the recent negative phase III trial investigating the addition of sunitinib to 5-FU and irinotecan in 1st line treatment of advanced colorectal cancer carcinoma (CRC) [4], this empirical ad hoc selection of suitable drug combinations www.impactjournals.com/oncotarget is costly and error prone It should preferably be substituted with a strategy based on knowledge gained from more comprehensive preclinical investigations. There is a great need for more comprehensive and sophisticated preclinical drug combination analyses and CRC in vitro models that more successfully can guide the selection of drug combinations suitable for a clinical testing [2, 5]
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