Abstract
The search for effective combination therapies for cancer has focused heavily on synergistic combinations because they exhibit enhanced therapeutic efficacy at lower doses. Although synergism is intuitively attractive, therapeutic success often depends on whether drug resistance develops. The impact of synergistic combinations (vs. antagonistic or additive combinations) on the process of drug-resistance evolution has not been investigated. In this study, we use a simplified computational model of cancer cell numbers in a population of drug-sensitive, singly-resistant, and fully-resistant cells to simulate the dynamics of resistance evolution in the presence of two-drug combinations. When we compared combination therapies administered at the same combination of effective doses, simulations showed synergistic combinations most effective at delaying onset of resistance. Paradoxically, when the therapies were compared using dose combinations with equal initial efficacy, antagonistic combinations were most successful at suppressing expansion of resistant subclones. These findings suggest that, although synergistic combinations could suppress resistance through early decimation of cell numbers (making them "proefficacy" strategies), they are inherently fragile toward the development of single resistance. In contrast, antagonistic combinations suppressed the clonal expansion of singly-resistant cells, making them "antiresistance" strategies. The distinction between synergism and antagonism was intrinsically connected to the distinction between offensive and defensive strategies, where offensive strategies inflicted early casualties and defensive strategies established protection against anticipated future threats. Our findings question the exclusive focus on synergistic combinations and motivate further consideration of nonsynergistic combinations for cancer therapy.Significance: Computational simulations show that if different combination therapies have similar initial efficacy in cancers, then nonsynergistic drug combinations are more likely than synergistic drug combinations to provide a long-term defense against the evolution of therapeutic resistance. Cancer Res; 78(9); 2419-31. ©2018 AACR.
Highlights
Modern cancer therapeutics have excellent initial efficacy, but resistance often develops in a span of months
We focus on kRS þ SR > 1, because some singly-resistant cells will continue to exist, permitting the question of how long until at least one transforms into resistant to both drugs (RR)
Under the Constant-Dose Method, synergism was more effective than antagonism at reducing cell numbers in the short term, and suppressing the growth of resistant cells in the long term (Fig. 2A)
Summary
Modern cancer therapeutics have excellent initial efficacy, but resistance often develops in a span of months. Investigating combination therapy for combating cancer resistance is currently of great interest in the clinical setting [1, 2], at the bench [3, 4], and in computational modeling [5,6,7,8,9]. As synergism by definition has the greatest potency relative to total dose, and as toxicity often increases monotonically with dose, much focus has been given to finding potent synergistic combinations. Combination toxicity is complex [11,12,13], and the side effects of multidrug treatments remain speculative. Antagonism is sometimes misconstrued as an "antidote" effect, where one drug cancels out the efficacy of another
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