A Systematic Review of Evidence for the Cost of Therapeutic Resistance in Cancer

Emergence of therapeutic resistance is a critical clinical challenge in cancer treatment, contributing to treatment failure, disease relapse, and overall poor prognosis. Adaptive therapy (AT), a resistance management strategy, aims to address this issue by selectively applying therapeutic pressure to promote competition between therapy-sensitive and therapy-resistant clones, allowing for long-term control of tumor burden. AT relies upon the assumption that resistance comes at some fitness cost in the absence of therapy. Is that assumption justified? We conducted a systematic review of the literature on experimental tests of the fitness cost of therapeutic resistance. We conducted a search for peer-reviewed papers that fulfilled the following selection criteria: (i) experiments of direct competition, (ii) between therapy-resistant and therapy-sensitive clones, (iii) in a therapy-free environment. We found 47 experiments that matched those criteria. Of those experiments, approximately two-thirds (68%) found a fitness cost to resistance in a competitive environment. Of all pooled features from the studies reviewed, we found that the resistance characteristic was most significantly associated with whether resistant clones exhibited a fitness advantage in competition (p=0.0147). Further, we identify complex ecological interactions that may influence the behavior of the cancer cell population without selection by therapeutic pressure. Predicting which resistance characteristics can be exploited therapeutically with AT and identifying potential methods of modulating the costliness of the resistant phenotype may be critical to future improvements in cancer therapy. Lay SummaryWhen cancer cells evolve to no longer respond to a cancer therapy, do they pay a cost for that invulnerability? We reviewed experiments where cancer cells resistant to a therapy were pitted against cancer cells that were still sensitive to the therapy. Approximately [2/3] of the experiments showed that the sensitive cells could out-compete the resistant cells, implying that the latter were paying some cost for their ability to resist the therapy.