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

Abstract

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.

Fig. 1. Functional diversity of aurora kinase A (AURKA).

AURKA is involved in a variety of biological pathways (green circled area), including cell cycle progression, mitosis, epigenetics, mitochondrial homeostasis, DNA replication, cilia disassembly, neurite elongation, and regulation of tumor suppressors and oncogenes, through interactions or kinase-substrate relationships with its partnering proteins (pink circled area).

Fig. 2. Two common mechanisms of aurora kinase A (AURKA) synthetic lethal interactions.

Synthetic lethal interactions of AURKA with the SNF5 and ARID1A tumor suppressors involve SWI/SNF-mediated transcriptional repression of AURKA. Loss of SNF5 or ARID1A derepresses AURKA transcription, and the elevated AURKA level in rhabdoid tumor (RT) or colorectal cancer (CRC) cells leads to AURKA oncogene addiction. AURKA-addicted RT and CRC cells are highly sensitive to agents targeting AURKA signaling. The synthetic lethal interactions of AURKA with the SMARCA4 and RB1 tumor suppressors involve cellular AURKA dependency. SMARCA4 is likely to play an essential role in centrosome-dependent spindle assembly, while it negatively regulates the centrosome-independent pathway. AURKA is essential in both pathways for spindle assembly. Loss of SMARCA4 drives cells to rely on the centrosome-independent pathway, which creates a cellular dependency on the function of AURKA in spindle assembly. Loss of RB1 primes spindle assembly checkpoint (SAC) activation in cells via E2F-mediated upregulation of the SAC protein MAD2 and microtubule destabilizer STMN1. Active AURKA in RB1-deficient cells mitigates STMN1-induced microtubule destabilization or overrides SAC activation for cell survival.