Dynamic phenotypic switching and group behavior help non-small cell lung
cancer cells evade chemotherapy
Abstract
Drug resistance, a major challenge in cancer therapy, is typically
attributed to mutations and genetic heterogeneity. On the other hand,
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 68 with cisplatin. We show
that the cisplatin-sensitive and cisplatin-tolerant NSCLC cells when
co69 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.