The impact of the spatial heterogeneity of resistant cells and fibroblasts on treatment response

A long-standing practice in the treatment of cancer is that of hitting hard with the maximum tolerated dose to eradicate tumors. This continuous therapy, however, selects for resistant cells, leading to the failure of the treatment. A different type of treatment strategy, adaptive therapy, has recently been shown to have a degree of success in both preclinical xenograft experiments and clinical trials. Adaptive therapy is used to maintain a tumors volume by exploiting the competition between drug-sensitive and drug-resistant cells with minimum effective drug doses or timed drug holidays. To further understand the role of competition in the outcomes of adaptive therapy, we developed a 2D on-lattice agent-based model. Our simulations show that the superiority of the adaptive strategy over continuous therapy depends on the local competition shaped by the spatial distribution of resistant cells. Cancer cell migration and increased carrying capacity accelerate the progression of the tumor under both types of treatments by reducing the spatial competition. Intratumor competition can also be affected by fibroblasts, which produce microenvironmental factors that promote cancer cell growth. Our simulations show that the spatial architecture of fibroblasts modulates the benefits of adaptive therapy. Finally, as a proof of concept, we simulated the outcomes of adaptive therapy in multiple metastatic sites composed of different spatial distributions of fibroblasts and drug-resistant cell populations.