Schematic of the simple model.

<p>Here we study the scenarios where drug concentration and the rate of cell proliferation can be spatially dependent on the tumor microenvironment and <i>de novo</i> resistance mutations are needed to escape potent treatments (<i>i.e.</i>, targeted combination therapies). (<b>A</b>) Even if only a small number of cells reside in the sanctuary and/or are slowly replicating, they persistently seed the non-sanctuary compartment that would have almost certainly become void otherwise. Therefore, resistance in the non-sanctuary compartment arises through two competing pathways: (<b>B</b>) the “migration-mutation” pathway in which sensitive cells first migrate to the harsh drug-containing compartment and then evolve resistance <i>in situ</i>, or (<b>C</b>) the “mutation-migration” pathway in which sensitive cells first acquire the resistant mutation in the sanctuary compartment and then migrate into and subsequently populate the drug-present compartment. We show that, under a wide variety of conditions, resistant cells thriving in compartments with high levels of drugs are likely to originate from sanctuary sites, where they acquired resistance preceding migration.