Aurora kinase A inhibition induces synthetic lethality in SMAD4-deficient colorectal cancer cells via spindle assembly checkpoint activation

• Published in: Oncogene 2022-05, Vol.41 (19), p.2734-2748
• Main Authors: Shi, Changxiang, Tao, Shishi, Ren, Guowen, Yang, Eun Ju, Shu, Xiaodong, Mou, Pui Kei, Liu, Yifan, Dang, Yongjun, Xu, Xiaoling, Shim, Joong Sup
• Format: Article
• Language: English
• Subjects: 13/1; 13/109; 38/89; 631/67/1059/602; 631/67/395; 64/60; 96/31; 96/95; 96/98; Aneuploidy; Apoptosis; Aurora kinase; Aurora Kinase A - genetics; Aurora Kinase A - metabolism; Cell Biology; Cell cycle; Cell Cycle Checkpoints - genetics; Cell death; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Drug screening; Human Genetics; Humans; Internal Medicine; Kinases; Lethality; M Phase Cell Cycle Checkpoints - genetics; Medicine; Medicine & Public Health; Oncology; Smad4 protein; Smad4 Protein - genetics; Smad4 Protein - metabolism; Spindles; Synthetic Lethal Mutations; Therapeutic targets
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-022-02293-y

SMAD4 loss-of-function mutations have been frequently observed in colorectal cancer (CRC) and are recognized as a drug target for therapeutic exploitation. In this study, we performed a synthetic lethal drug screening with SMAD4 -isogenic CRC cells and found that aurora kinase A (AURKA) inhibition is synthetic lethal with SMAD4 loss. Inhibition of AURKA selectively inhibited the growth of SMAD4 −/− CRC in vitro and in vivo. Mechanistically, SMAD4 negatively regulated AURKA level, resulting in the significant elevation of AURKA in SMAD4 −/− CRC cells. Inhibition of AURKA induced G 2 /M cell cycle delay in SMAD4 +/+ CRC cells, but induced apoptosis in SMAD4 −/− CRC cells. We further observed that a high level of AURKA in SMAD4 −/− CRC cells led to abnormal mitotic spindles, leading to cellular aneuploidy. Moreover, SMAD4 −/− CRC cells expressed high levels of spindle assembly checkpoint (SAC) proteins, suggesting the hyperactivation of SAC. The silencing of key SAC proteins significantly rescued the AURKA inhibition-induced cell death in SMAD4 −/− cells, suggesting that SMAD4 −/− CRC cells are hyper-dependent on AURKA activity for mitotic exit and survival during SAC hyperactivation. This study presents a unique synthetic lethal interaction between SMAD4 and AURKA and suggests that AURKA could be a potential drug target in SMAD4-deficient CRC.