Disclosure of Conflict of Interest: C.M. O'Connor and G. Narla are named inventors on a US provisional patent application concerning compositions and methods for treating high grade subtypes of uterine cancer. C.M. O'Connor, T.K. Suhan, K.P. Zawacki, and J. Sangodkar are consultants for RAPPTA Therapeutics. G. Narla is chief scientific officer at RAPPTA Therapeutics, is an SAB member at Hera BioLabs, reports receiving commercial research support from RAPPTA Therapeutics, and has ownership interest (including patents) in RAPPTA Therapeutics. D. Zamarin reports research support to his institution from Astra Zeneca, Plexxikon, and Genentech; personal/consultancy fees from Synlogic Therapeutics, GSK, Genentech, Xencor, Memgen, Immunos, Celldex, Calidi, and Agenus. D. Zamarin is an inventor on a patent related to use of oncolytic Newcastle Disease Virus for cancer therapy.Research.

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Supplementary Table from Targeting Ribonucleotide Reductase Induces Synthetic Lethality in PP2A-Deficient Uterine Serous Carcinoma

Supplementary Figure from Targeting Ribonucleotide Reductase Induces Synthetic Lethality in PP2A-Deficient Uterine Serous Carcinoma

<div>Abstract<p>Uterine serous carcinoma (USC) is a highly aggressive endometrial cancer subtype with limited therapeutic options and a lack of targeted therapies. While mutations to <i>PPP2R1A</i>, which encodes the predominant protein phosphatase 2A (PP2A) scaffolding protein Aα, occur in 30% to 40% of USC cases, the clinical actionability of these mutations has not been studied. Using a high-throughput screening approach, we showed that mutations in Aα results in synthetic lethality following treatment with inhibitors of ribonucleotide reductase (RNR). <i>In vivo</i>, multiple models of Aα mutant uterine serous tumors were sensitive to clofarabine, an RNR inhibitor (RNRi). Aα-mutant cells displayed impaired checkpoint signaling upon RNRi treatment and subsequently accumulated more DNA damage than wild-type (WT) cells. Consistently, inhibition of PP2A activity using LB-100, a catalytic inhibitor, sensitized WT USC cells to RNRi. Analysis of The Cancer Genome Atlas data indicated that inactivation of PP2A, through loss of PP2A subunit expression, was prevalent in USC, with 88% of patients with USC harboring loss of at least one PP2A gene. In contrast, loss of PP2A subunit expression was rare in uterine endometrioid carcinomas. While RNRi are not routinely used for uterine cancers, a retrospective analysis of patients treated with gemcitabine as a second- or later-line therapy revealed a trend for improved outcomes in patients with USC treated with RNRi gemcitabine compared with patients with endometrioid histology. Overall, our data provide experimental evidence to support the use of ribonucleotide reductase inhibitors for the treatment of USC.</p>Significance:<p>A drug repurposing screen identifies synthetic lethal interactions in PP2A-deficient uterine serous carcinoma, providing potential therapeutic avenues for treating this deadly endometrial cancer.</p></div>

Supplementary Data from Targeting Ribonucleotide Reductase Induces Synthetic Lethality in PP2A-Deficient Uterine Serous Carcinoma

Supplementary Table from Targeting Ribonucleotide Reductase Induces Synthetic Lethality in PP2A-Deficient Uterine Serous Carcinoma

Supplementary Data from Targeting Ribonucleotide Reductase Induces Synthetic Lethality in PP2A-Deficient Uterine Serous Carcinoma