Drug resistance and tumor heterogeneity: cells and ensembles.

The population of cells that make up a tumor, and of their biomolecular conformational ensembles, are heterogeneous at all levels, genetic, epigenetic, and phenotypic. At the cellular level, tumor heterogeneity was described as the "Rosetta Stone of therapy resistance." At the genetic level, tumors consist of divergent tumor (sub)clones. At the phenotypic level, their observed function, clinical attributes, and response to drugs vary. We suggest that the behavior and properties of populations of cells-and of populations of conformational states-are intrinsically connected. This is important. Considering the tumor's disruption of normal cellular processes clarifies why it is crucial to understand the ins and outs of its mechanistic molecular foundation. In reality, the propensities of the tumor's conformational states underly the proliferative potential of its cell populations. These propensities are determined by expression levels, driver mutations, and the tumor cells environment, collectively transforming tumor cells behavior and crucially, drug resistance. We suggest that propensities of the conformations, across the tumor space and over time, shape tumor heterogeneity, and cell plasticity. The conformational states that are preferentially visited can be viewed as phenotypic determinants, and their mutations and altered expression work by allosterically shifting the relative propensities, thus the cell phenotype. Physics (and chemistry) inspire the notion that living things must conform to fundamental laws of science, like dynamic landscapes. Dynamic conformational propensities are at the core of cell life, including tumor cells; their heterogeneity is the formidable, unmet drug resistance challenge.