A model for the intrinsic limit of cancer therapy: Duality of treatment-induced cell death and treatment-induced stemness

Author summaryAdvance in the war on cancer is concentrated at one single front: more efficient killing of tumor cells, including by targeted or immuno-therapy. However, cells are hard-wired to activate regenerative or protective programs in response to near-lethal stress. Thus, cancer cells not killed during treatment are still stressed and often enter a stem-like state. This "double-edged-sword" effect (conflict between killing and strengthening by treatment) establishes an intrinsic limit to all cell-killing therapies. To optimize therapy a mathematical framework considering key quantitative parameters of treatment is necessary to predict which way the double-edged-sword will cut. Here we present an analytical model that define the parameter regimes in which tumor eradication either can or fundamentally cannot be achieved, but containment can be maximized. Intratumor cellular heterogeneity and non-genetic cell plasticity in tumors pose a recently recognized challenge to cancer treatment. Because of the dispersion of initial cell states within a clonal tumor cell population, a perturbation imparted by a cytocidal drug only kills a fraction of cells. Due to dynamic instability of cellular states the cells not killed are pushed by the treatment into a variety of functional states, including a "stem-like state" that confers resistance to treatment and regenerative capacity. This immanent stress-induced stemness competes against cell death in response to the same perturbation and may explain the near-inevitable recurrence after any treatment. This double-edged-sword mechanism of treatment complements the selection of preexisting resistant cells in explaining post-treatment progression. Unlike selection, the induction of a resistant state has not been systematically analyzed as an immanent cause of relapse. Here, we present a generic elementary model and analytical examination of this intrinsic limitation to therapy. We show how the relative proclivity towards cell death versus transition into a stem-like state, as a function of drug dose, establishes either a window of opportunity for containing tumors or the inevitability of progression following therapy. The model considers measurable cell behaviors independent of specific molecular pathways and provides a new theoretical framework for optimizing therapy dosing and scheduling as cancer treatment paradigms move from "maximal tolerated dose," which may promote therapy induced-stemness, to repeated "minimally effective doses" (as in adaptive therapies), which contain the tumor and avoid therapy-induced progression.