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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

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Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA
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Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA 02215, USA
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Department of Biochemistry, Cambridge University, Cambridge CB2 1QW, UK
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Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
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Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA
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Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA
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Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA 02115, USA
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Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, MA 02115, USA
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Department of Pathology, Harvard Medical School, Boston, MA 02115, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Izumi Horikawa
Cancers 2021, 13(9), 2195; https://doi.org/10.3390/cancers13092195
Received: 28 March 2021 / Revised: 27 April 2021 / Accepted: 30 April 2021 / Published: 3 May 2021
(This article belongs to the Section Molecular Cancer Biology)
Cancers arising from the lining of the uterus, endometrial cancers, are the most common gynecologic malignancy in the United States. Once endometrial cancer escapes the uterus and grows in distant locations, there are limited therapeutic options. The most aggressive and lethal endometrial cancers carry alterations in the protein p53, which is a critical guardian of many cellular functions. The role of these p53 alterations in endometrial cancer is not well understood. The goal of this work was to use p53 altered models of endometrial cancer to understand which, if any, therapeutically targetable vulnerabilities these p53 alterations may confer in endometrial cancer. Here we show that many of these p53 altered cells have problems with cell division which can be targeted with novel single and combination therapies. These discoveries may lead to relevant new therapies for difficult to treat advanced stage endometrial cancers.
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. View Full-Text
Keywords: Aurora kinase; LKB1; uterine cancer; p53; G2/M cell cycle checkpoint Aurora kinase; LKB1; uterine cancer; p53; G2/M cell cycle checkpoint
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MDPI and ACS Style

Lynch, K.N.; Liu, J.F.; Kesten, N.; Chow, K.-H.; Shetty, A.; He, R.; Afreen, M.F.; Yuan, L.; Matulonis, U.A.; Growdon, W.B.; Muto, M.G.; Horowitz, N.S.; Feltmate, C.M.; Worley, M.J., Jr.; Berkowitz, R.S.; Crum, C.P.; Rueda, B.R.; Hill, S.J. 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 2021, 13, 2195. https://doi.org/10.3390/cancers13092195

AMA Style

Lynch KN, Liu JF, Kesten N, Chow K-H, Shetty A, He R, Afreen MF, Yuan L, Matulonis UA, Growdon WB, Muto MG, Horowitz NS, Feltmate CM, Worley MJ Jr., Berkowitz RS, Crum CP, Rueda BR, Hill SJ. 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. 2021; 13(9):2195. https://doi.org/10.3390/cancers13092195

Chicago/Turabian Style

Lynch, Katherine N.; Liu, Joyce F.; Kesten, Nikolas; Chow, Kin-Hoe; Shetty, Aniket; He, Ruiyang; Afreen, Mosammat F.; Yuan, Liping; Matulonis, Ursula A.; Growdon, Whitfield B.; Muto, Michael G.; Horowitz, Neil S.; Feltmate, Colleen M.; Worley, Michael J., Jr.; Berkowitz, Ross S.; Crum, Christopher P.; Rueda, Bo R.; Hill, Sarah J. 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, no. 9: 2195. https://doi.org/10.3390/cancers13092195

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