How Compensatory Mechanisms and Adaptive Rewiring Have Shaped Our Understanding of Therapeutic Resistance in Cancer

Abstract

Therapeutic resistance to targeted therapies by tumor cells is a common and serious problem in the clinic. Increased understanding of the molecular mechanisms that underly resistance is necessary for the rational design and improvement of effective pharmacologic treatment strategies. The landmark study by O'Reilly and colleagues published in Cancer Research in 2006 provided valuable insights into nongenomic adaptive rewiring and compensatory mechanisms responsible for mediating resistance to targeted inhibition of the PI3K-AKT-mTOR pathway, and how tumor cells regulate signaling pathways via negative feedback loops. These findings have proven fundamental for guiding current efforts to develop effective combination treatments and provided a blueprint for research studies aimed at understanding the intricacies of cellular signaling.See related article by O'Reilly and colleagues, Cancer Res 2006;66:1500-8.

Figure 1.

Signaling through the PI3K-AKT-mTOR pathway is regulated at multiple nodes via negative feedback loops and compensatory mechanisms. Activation of mTORC1 induces down-regulation of IRS1/2 (1), thereby inhibiting PI3K activation by the insulin and IGF1 receptors (InsR/IGF1R). In addition, mTORC1 directly phosphorylates and stabilizes Grb10 (2), which acts to inhibit signaling from the InsR/IGF1R to IRS1/2. Signaling via mTORC1 also inhibits mTORC2 through phosphorylation by S6K (3), thus inhibiting AKT phosphorylation on S473. Furthermore, activated AKT inhibits FOXO-mediated up-regulation of receptor tyrosine kinases (RTKs), including EGFR, HER3 and InsR/IGF1R (4). CDK4/6-Cyclin D complexes inhibit mTORC1 signaling via phosphorylation and inhibition of TSC2 (5). Disruption of these negative feedback loops by pharmacological inhibitors induces up-regulation of compensatory mechanism that may lead to adaptive resistance. Finally, tumor cells can also respond to pharmacological PI3K pathway inhibition by stimulating PI3K-independent oncogenic signaling. For example, enhanced FOXO-mediated RTK expression resulting from AKT down-regulation can up-regulate ERK signaling (6).