Aurora kinase A, a synthetic lethal target for precision cancer medicine

摘要

Recent advances in high-throughput sequencing technologies and data science have facilitated the development of precision medicine to treat cancer patients. Synthetic lethality is one of the core methodologies employed in precision cancer medicine. Synthetic lethality describes the phenomenon of the interplay between two genes in which deficiency of a single gene does not abolish cell viability but combined deficiency of two genes leads to cell death. In cancer treatment, synthetic lethality is leveraged to exploit the dependency of cancer cells on a pathway that is essential for cell survival when a tumor suppressor is mutated. This approach enables pharmacological targeting of mutant tumor suppressors that are theoretically undruggable. Successful clinical introduction of BRCA-PARP synthetic lethality in cancer treatment led to additional discoveries of novel synthetic lethal partners of other tumor suppressors, including p53, PTEN, and RB1, using high-throughput screening. Recent work has highlighted aurora kinase A (AURKA) as a synthetic lethal partner of multiple tumor suppressors. AURKA is a serine/threonine kinase involved in a number of central biological processes, such as the G2/M transition, mitotic spindle assembly, and DNA replication. This review introduces synthetic lethal interactions between AURKA and its tumor suppressor partners and discusses the potential of AURKA inhibitors in precision cancer medicine. Cancer: Targeting gene combinations to kill tumors Synthetic lethality, which arises when two genes whose functions are related in such a way that a cancer cell can survive a deficiency in one but not in both, is emerging as a viable approach to treat cancers previously regarded as not treatable by drugs. Joong Sup Shim and colleagues at the University of Macau, China, review a promising synthetic lethality strategy centered on an enzyme called AURKA that is involved in many key biological processes. If a tumor is identified as already having a deficiency in a particular gene, using a drug to inhibit the AURKA enzyme produced by a different gene can lead to cancer cell death. This is an example of personalised medicine, as it depends on identifying specific mutations in a patient’s tumor that make it vulnerable to the synthetic lethality approach.