Back to the future: mechanism-based, mutation-specific combination chemoprevention with a synthetic lethality approach

Abstract

There is an increasing recognition that the mutations accompanying carcinogenesis may provide a window of therapeutic advantage designated synthetic lethality, an example of which is reported in this issue of the journal by Huang and colleagues (beginning on page 666). First discovered and studied in yeast, synthetic lethality has basic principles that have encouraged its development for treatment and now prevention in animal models of human cancer, especially malignancies refractory to standard approaches. The pros and cons of this approach and challenges in implementing it clinically are discussed.

Figure 1

A, a simplified example of synthetic lethality induced pharmacologically with TRAIL plus Smac mimic. The general synthetic lethality concept is that mutations in cancer cells prevent their ability to recover from inhibition of a reexpressed or alternative pathway; this effect potentially would lead to an enhanced risk/benefit ratio of intervention because normal cells should be unaffected or minimally affected. Theoretically, the biochemical or molecular targets could be at the RNA, iRNA, protein, enzyme, or epigenetic level, and inhibitors could include siRNAs, small molecules, and targeted nanoparticles. WT, wild type. B, mutant KRAS-induced lung premalignancy. Mutant KRAS activates c-MYC [which suppresses FLICE-like inhibitory protein (cFLIP)] and downregulates decoy receptors, which sensitizes the death receptor (DR) pathway to TRAIL activation (binding DR4/5 and activating caspase 8/10). Smac mimic inhibits XIAP, thus activating caspase 3, which induces cell death by apoptosis. WT, wild type.