Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1–AKT–p53 Interactions
Liu, Joyce F.
Afreen, Mosammat Faria
Matulonis, Ursula A.
Growdon, Whitfield B.
Muto, Michael G.
Horowitz, Neil S.
Feltmate, Colleen M.
Worley, Michael J.
Berkowitz, Ross S.
Crum, Christopher P.
Rueda, Bo R.
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Lynch, K. N., Liu, J. F., Kesten, N., Chow, K., Shetty, A., He, R., Afreen, M. F., et al. (2021). Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1–AKT–p53 Interactions. Cancers, 13 (9)https://doi.org/10.3390/cancers13092195
Uterine carcinoma (UC) is the most common gynecologic malignancy in the United States. TP53 mutant UCs cause a disproportionate number of deaths due to limited therapies for these tumors and the lack of mechanistic understanding of their fundamental vulnerabilities. Here we sought to understand the functional and therapeutic relevance of TP53 mutations in UC. We functionally profiled targetable TP53 dependent DNA damage repair and cell cycle control pathways in a panel of TP53 mutant UC cell lines and patient-derived organoids. There were no consistent defects in DNA damage repair pathways. Rather, most models demonstrated dependence on defective G2/M cell cycle checkpoints and subsequent upregulation of Aurora kinase-LKB1-p53-AKT signaling in the setting of baseline mitotic defects. This combination makes them sensitive to Aurora kinase inhibition. Resistant lines demonstrated an intact G2/M checkpoint, and combining Aurora kinase and WEE1 inhibitors, which then push these cells through mitosis with Aurora kinase inhibitor-induced spindle defects, led to apoptosis in these cases. Overall, this work presents Aurora kinase inhibitors alone or in combination with WEE1 inhibitors as relevant mechanism driven therapies for TP53 mutant UCs. Context specific functional assessment of the G2/M checkpoint may serve as a biomarker in identifying Aurora kinase inhibitor sensitive tumors.
Aurora kinase, LKB1, uterine cancer, p53, G2/M cell cycle checkpoint
NIH Office of the Director (DP5 OD029637)
External DOI: https://doi.org/10.3390/cancers13092195
This record's URL: https://www.repository.cam.ac.uk/handle/1810/321933