Induction of Synthetic Lethality by Natural Compounds Targeting Cancer Signaling

Despite the breakthroughs that have been achieved, significant unmet needs relating to the inadequate efficacy and toxicity of currently-available cancer therapies remain. Kinase inhibitors are a class of agents that target signaling factors responsible for the survival of malignant cells, and may address at least some of these issues. The concept of synthetic lethality provides a potential solution to counteract pathway redundancies, and refers to situations in which a mutation in one of two particular genes alone permits cell survival, while simultaneous mutation in both results in cell death. When exploited in the context of cancer therapy, pathways that are uniquely upregulated in cancer cells become selective targets, with reduced off-target toxicity toward their healthy counterparts. Natural compounds represent a large and readily-accessible library of bioactive structures that can be screened for synthetically lethal interactions by testing for the inhibition of kinases relevant to cancer cell survival. In this review, we discuss the concept of synthetic lethality and focus on scenarios in which natural compounds that target kinases may be applied to tip the balance in favor of cancer cell death during therapeutic challenge.