The Double-Edged Role of Enzyme Inhibition in Oral Anticancer Therapy

Oral anticancer therapy is built on the deliberate inhibition of enzymes that drive malignant growth, among them protein kinases, poly(ADP-ribose) polymerases, cyclin-dependent kinases 4 and 6, the PI3K/AKT/mTOR and BRAF/MEK cascades, histone deacetylases and the proteasome. The same molecules are processed by the enzymes that metabolize drugs, and several of them inhibit or induce those enzymes in turn. Enzyme inhibition therefore carries two faces, and the objective of this review is to examine them as a single pharmacological phenomenon rather than as two separate subjects. The argument proposed is that the two are causally linked, because the structural features allowing a molecule to occupy a catalytic site also determine which metabolizing enzymes recognize it. Three consequences organize the review. Agents sharing a therapeutic target can differ by more than an order of magnitude in their dependence on one metabolizing enzyme, meaning that interaction liability is a property of the molecule rather than of its class. The mechanism of inhibition, whether reversible, covalent or time-dependent, governs how long an interaction persists. Several oral anticancer agents are themselves inhibitors or inducers of drug-metabolizing enzymes, acting as perpetrators rather than victims. Each point is quantified for representative agents from regulatory pharmacology data.