Abstract
Drug resistance, a major challenge in cancer therapy, is typically attributed to mutations and genetic heterogeneity. Emerging evidence suggests that dynamic cellular interactions and group behavior also contribute to drug resistance. However, the underlying mechanisms remain poorly understood. Here, we present a new mathematical approach with game theoretical underpinnings that we developed to model real-time growth data of non-small cell lung cancer (NSCLC) cells and discern patterns in response to treatment with cisplatin. We show that the cisplatin-sensitive and cisplatin-tolerant NSCLC cells, when co-cultured in the absence or presence of the drug, display dynamic group behavior strategies. Tolerant cells exhibit a ‘persister-like’ behavior and are attenuated by sensitive cells; they also appear to ‘educate’ sensitive cells to evade chemotherapy. Further, tolerant cells can switch phenotypes to become sensitive, especially at low cisplatin concentrations. Finally, switching treatment from continuous to an intermittent regimen can attenuate the emergence of tolerant cells, suggesting that intermittent chemotherapy may improve outcomes in lung cancer.
Highlights
Drug resistance in cancer is generally believed to arise stochastically through random genetic mutations and the subsequent expansion of mutant clones via Darwinian selection [1,2]
Employing PSMSR, we showed that, quantitatively, the two cell populations, when co-cultured in the absence of cisplatin, display dynamic group behavior that can be interpreted using evolutionary game theory concepts as payoffs
We demonstrate that switching treatments from a continuous to an intermittent regimen can attenuate the emergence of tolerant cells, underscoring a potentially new treatment option that could benefit patients with non-small cell lung cancer (NSCLC)
Summary
Drug resistance in cancer is generally believed to arise stochastically through random genetic mutations and the subsequent expansion of mutant clones via Darwinian selection [1,2]. We have used human non-small cell lung cancer (NSCLC) cells that are sensitive or tolerant to cisplatin, one of the most commonly used chemotherapeutics, to understand the role of group behavior in the emergence of drug-tolerant clones, and eventually resistant clones. These experiments would have been performed using cell lines that have a common evolutionary origin, e.g., from the same patient. Initial success of the intermittent therapy in zebrafish, as shown in this work, suggests that our observations could be relevant in vivo
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