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

Abstract

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.

Targeting protein phosphatases for the treatment of inflammation-related diseases: From signaling to therapy

“… 239 In 2020, the derivative of SHP099, TNO155, went into clinical trial for the treatment solid tumor. 240 In addition to PTP1B and SHP2 inhibitors, there are few drugs targeting other phosphatases, and only a few drugs such as PRL3-zumab 241 (anti-PRL3 antibody), and LB-100 242 (PP2A inhibitor) have advanced to the clinical stage (Fig. 2 , Table 3 ).…”

The PPP2R1A cancer hotspot mutant p.R183W increases clofarabine resistance in uterine serous carcinoma cells by a gain-of-function mechanism

“…To date, nucleoside analogues are not routinely considered as treatment for patients with EC, although gemcitabine is sometimes used as a second-line or later-line therapy [24]. With this study, we showed that nucleoside analogues show potential to become a more valuable treatment option for patients with type II EC and should be investigated more thoroughly in pre-clinical studies.…”

“…Conversely, Aα WT overexpression in the PPP2R1A mutant cell lines resulted in increased resistance towards clofarabine. Therefore, this study suggested the use of the PPP2R1A mutational status as a positive predictive marker for treatment of EC patients with clofarabine [24].…”

“…Despite signi cant promise, studies on the clinical actionability of the PPP2R1A hotspot mutations remain scarce, and PPP2R1A mutation status is not yet included in the strati cation criteria for clinical trials, as opposed to HER2 (e.g., ongoing clinical trial: NCT05256225). Recently, however, over 3000 compounds were screened in type II USC cell models, expressing wild-type (WT) or mutant Aα [24]. This screening revealed synthetic lethality in cells harboring the p.P179R or p.S256F Aα hotspot variants when treated with the FDA-approved nucleoside analogue clofarabine.…”

Biased holoenzyme assembly of protein phosphatase 2A (PP2A): From cancer to small molecules

“…Additionally, loss of PTPA was found to sensitize to mTOR inhibitors, loss of B55α ( PPP2R2A ) and B56α ( PPP2R5A ) sensitized to poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) (veliparib), Checkpoint Kinase 1 (Chk1) inhibitors (SB218078), and ATR inhibitors ( 185 , 186 , 187 , 188 , 189 , 190 ). Lastly, PP2A Aα mutants were found to sensitize to ribonucleotide reductase inhibitors, including Gemcitabine and Clofarabine ( 191 ). Collectively, these approaches illustrate that PP2A-inactivated tumors may be targeted using synthetic lethal based strategies, and PP2A activity may play a significant role in the development of therapy resistance.…”