Researchers identified a highly recurrent, disease-specific PP2A PPP2R1A mutation as a driver of endometrial carcinoma and as a target for new drugs, as detailed in a study published in Cancer Research.
“This work stands out from many other studies that evaluate mutations in genes associated with cancer in that (it studies) the mutation at a DNA, RNA, and protein level as opposed to many other works that may only characterize one or two of these,” said Sarah E. Taylor, study author, gynecological oncologist at UPMC Hillman Cancer Center and assistant professor of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, in an interview with Cancer Network. “Additionally, (the study) characterizes both a unique mechanism of action as a tumor driver, as well as demonstrate a potential therapeutic intervention... This is an exciting start to a potential new target in two cancer subtypes that are need of new and effective therapeutic interventions. Additional work needs to be done to be able to translate these findings into a human population so that this work can be leveraged to treat women with uterine cancer.”
The study found that somatic mutation of the protein phosphatase 2A (PP2A) Aα-subunit gene PPP2R1A is very frequent in high-grade endometrial carcinoma. The mechanistic basis by which the most recurrent endometrial carcinoma–specific mutation site P179 mediates features of endometrial carcinoma malignancy has yet to be elucidated in full.
A series of structural, biochemical, and biological strategies were used to uncover the effects of the P179R missense mutation on PP2A function. Results from modeling demonstrated that arginine-to-proline substitution at the P179 residue alters the protein's stable conformation profile. Furthermore, a crystal structure of the tumor-derived PP2A mutant displayed substantial changes in A-subunit conformation.
At the PP2A catalytic subunit, binding was markedly impaired, thus interfering holoenzyme formation and enzymatic activity. The team observed that cancer cells required disruption in PP2A for sustained carcinogenesis. Importantly, the restoration of wild-type Aα in a P179R-mutant patient cell line reestablished enzyme function and mitigated tumorigenesis and metastasis in vivo. Moreover, small molecule–mediated therapeutic reactivation of PP2A significantly prevented tumorigenicity in vivo.
“One of the most common alterations found in high-grade endometrial cancer is in the protein phosphatase 2A (PP2A), a ubiquitous serine/threonine phosphatase that negatively regulates diverse signaling cascades, including AKT, WNT, and c-MYC signaling pathways,” per the authors of an accompanying commentary, led by Kaitlin Haines, MD, Department of Obstetrics, Gynecology & Reproductive Sciences, Yale School of Medicine, Yale University, New Haven. “PPP2R1A encodes the PP2A-Aa subunit; mutations in this gene lead to diminished phosphatase activity and have been found in a broad spectrum of cancers.”