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.

Katherine N Lynch,Colleen M Feltmate,Ruiyang He,Michael J Worley,Neil S Horowitz,Nikolas Kesten,Kin-Hoe Chow,Whitfield B Growdon,Ross S Berkowitz,Christopher P Crum,Michael G Muto,Joyce F Liu,Ursula A Matulonis,Mosammat Faria Afreen,Aniket Shetty,Bo R Rueda,Sarah J Hill,Liping Yuan

doi:10.3390/cancers13092195

Abstract

Simple SummaryCancers 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.

Highlights

Uterine carcinoma (UC) is the most common gynecologic malignancy in the UnitedStates with high-grade endometrioid and serous subtypes, which are typically TP53 mutant, being the most lethal and difficult to treat [1,2]
Since p53 is a master regulator of the cell cycle and survival amid DNA damage, we asked whether high-grade TP53 mutant UCs harbor defects in DNA damage repair (DDR) increasing susceptibility to DDR targeted therapies [7,8,9], which target defects in repair of double strand
To functionally assess these pathways in TP53 mutant UCs, we compiled a panel of TP53 mutant UC cell lines and established multiple patient-derived organoids (PDOs)

Summary

Introduction

States with high-grade endometrioid and serous subtypes, which are typically TP53 mutant, being the most lethal and difficult to treat [1,2]. Once these tumors spread beyond the uterus, limited therapeutic options exist, largely due to our minimal understanding of the major mechanistic defects and drivers of this disease [3]. TP53 mutations are one of the most common genomic alterations across all high-grade. P53 has been widely studied across every malignancy and has many functions during cellular stress, including cell cycle arrest or apoptosis after DNA damage [7,8,9].

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