Fig. 7.

Schematic representation of drug sensitivity and tolerance in SUM149-derived models. Cancer cells have inherently high levels of ROS due to oncogenic signals and altered metabolism compared to normal cells. Presence of therapeutic insults/cellular stress can cause further increase in ROS, which in the absence of adaptive mechanism is associated with drug sensitivity and induction of cell death (SUM149). However, chronic stress leads to redox adaptive mechanisms such as increases in survival factors and antioxidants/ROS scavenging systems. These cells can suppress therapy-mediated ROS induction and/or rapidly clear ROS, which selects for a phenotypically distinct drug tolerant subpopulation of cells (rSUM149) that are drug tolerant due to their ROS protective mechanisms and contributes to multidrug resistance. Drug tolerance in this population of cells can be reversed by removal of the therapeutic stress for an extended period; loss of their redox adaptive mechanisms renders the resistant reversal cells (rrSUM149) highly therapy-sensitive.