Mitotic syndicates Aurora Kinase B (AURKB) and mitotic arrest deficient 2 like 2 (MAD2L2) in cohorts of DNA damage response (DDR) and tumorigenesis

Abstract

Aurora Kinase B (AURKB) and Mitotic Arrest Deficient 2 Like 2 (MAD2L2) are emerging anticancer therapeutic targets. AURKB and MAD2L2 are the least well studied members of their protein families, compared to AURKA and MAD2L1. Both AURKB and MAD2L2 play a critical role in mitosis, cell cycle checkpoint, DNA damage response (DDR) and normal physiological processes. However, the oncogenic roles of AURKB and MAD2L2 in tumorigenesis and genomic instability have also been reported. DDR acts as an arbitrator for cell fate by either repairing the damage or directing the cell to self-destruction. While there is strong evidence of interphase DDR, evidence of mitotic DDR is just emerging and remains largely unelucidated. To date, inhibitors of the DDR components show effective anti-cancer roles. Contrarily, long-term resistance towards drugs that target only one DDR target is becoming a challenge. Targeting interactions between protein-protein or protein-DNA holds prominent therapeutic potential. Both AURKB and MAD2L2 play critical roles in the success of mitosis and their emerging roles in mitotic DDR cannot be ignored. Small molecule inhibitors for AURKB are in clinical trials. A few lead compounds towards MAD2L2 inhibition have been discovered. Targeting mitotic DDR components and their interaction is emerging as a potent next generation anti-cancer therapeutic target. This can be done by developing small molecule inhibitors for AURKB and MAD2L2, thereby targeting DDR components as anti-cancer therapeutic targets and/or targeting mitotic DDR. This review focuses on AURKB and MAD2L2 prospective synergy to deregulate the p53 DDR pathway and promote favourable conditions for uncontrolled cell proliferation.

Keywords: Aurora Kinase B (AURKB); DNA damage response (DDR); Mitotic arrest deficient 2 like 2 (MAD2L2); Small molecule inhibitor; Spindle assembly checkpoint (SAC); p53.