Molecular glue RPT04402 stabilizes tumor-suppressing PP2A protein in lung and uterine cancer studies

One of the most quietly powerful tumor suppressors in human biology is also one of the most fragile. Protein phosphatase 2A, better known as PP2A, sits at the center of a web of cell signaling pathways that govern how cells grow, divide and die, and these pathways are among the most frequently disrupted during tumor development and growth. What makes PP2A unusual is its architecture: the enzyme is built from three separate proteins that must bind to one another in a precise trimer before it can function properly and hold cancers in check.

When that assembly fails, the tumor-suppressing activity collapses. Researchers at the University of Michigan report that this failure to assemble is commonly seen in lung, uterine, prostate and liver cancer, and that a small molecule designed to act as a molecular glue can hold the complex together, restoring its ability to suppress the growth of cancer cells in two new peer-reviewed studies. The compound, called RPT04402, acts as a molecular glue that helps the PP2A protein retain its structure.

In a study published in The Journal of Clinical Investigation, the team showed that targeting PP2A with RPT04402 can help treat non-small cell lung cancers that carry mutations in the KRAS gene, one of the most notorious drivers of human cancer. KRAS is important for cell growth and division, and it is mutated in roughly 30 percent of non-small cell lung cancer cases. Patients whose tumors harbor these mutations tend to have shorter survival times and often become resistant to the therapies designed against them, a clinical pattern that has frustrated oncologists for years.

Lung cancer is the second-most common cancer and the leading cause of cancer death in the United States, and more than 80 percent of lung cancers are non-small cell lung cancers, in which tumor cells are larger and grow more slowly than those in small cell lung cancer. There are several FDA-approved drugs that target KRAS in pancreatic, colon and lung cancer, said Goutham Narla, Louis Newburgh Research Professor of Internal Medicine and member of the Rogel Cancer Center at the University of Michigan. Although they work well, tumor cells gain resistance after a short period of time, he noted, a durability problem that has limited the long-term benefit of these targeted therapies for many patients.

The Michigan team uncovered what may be a hidden mechanism behind that resistance. Using cell lines of non-small cell lung cancers with KRAS mutations, the researchers showed that the anti-cancer drugs adagrasib, a KRAS inhibitor, and trametinib, which blocks the MAPK signaling pathway downstream of KRAS, both destabilized the PP2A complex. In other words, the very therapies meant to shut down KRAS-driven tumors appear to strip away a natural tumor suppressor at the same time.

That finding could explain why patients eventually become resistant to these treatments. However, when RPT04402 was added to the mix, the PP2A complex stabilized and the cancer cells died, suggesting the molecular glue could convert a destabilizing side effect into a lethal vulnerability for the tumor. The researchers confirmed these findings in mouse models of KRAS-mutant non-small cell lung cancer and found that the molecular glue caused tumors to shrink.

More strikingly, the combination of adagrasib or trametinib with RPT04402 delayed the emergence of resistance and increased the treatment effectiveness to over 150 days in mice, a substantial extension compared with the drugs alone. The result points to a rational combination strategy in which the molecular glue protects the PP2A trimer that conventional targeted therapies inadvertently destabilize, keeping the tumor-suppressing machinery intact while the KRAS and MAPK inhibitors do their work against the signaling pathways that drive tumor growth. The team is careful about the limits of the preclinical evidence.

Although we tested several cell lines and animal models, we don't know whether this combination will work in every case of non-small cell lung cancer, Narla said. Our findings represent a new approach to treat up to 20 to 30 percent of all non-small cell lung cancer cases, he added, referring to the fraction of tumors that carry KRAS mutations. The researchers plan to start clinical trials in collaboration with Spring Works Therapeutics and Merck, and they hope to extend the study to include other KRAS-mutant tumors, evaluating whether the drug combination works in pancreatic and colon cancers, where KRAS mutations are also prevalent and where the same resistance patterns have been observed clinically.

The second study, published in Science Translational Medicine, extends the molecular glue strategy to one of the most aggressive and underserved malignancies in women's health. The incidence and mortality rates of uterine cancer have been steadily increasing, specifically for aggressive high-grade types. Uterine cancer is now the most common cancer of the female reproductive system and the deadliest gynecological malignancy, a statistical shift that has alarmed gynecologic oncologists.

Current treatment methods include surgery and immunotherapy, but most high-grade uterine cancer patients either do not respond to treatment or their tumors recur, leaving a large population with few effective options after the initial standard of care fails. Against that backdrop, the Michigan researchers identified recurrent PP2A mutations as drivers of the development of aggressive uterine cancer, making the trimeric enzyme a direct therapeutic target rather than a collateral casualty of other drugs. In the Science Translational Medicine study, the team reported that RPT04402 can restore PP2A's ability to suppress the growth of uterine cancer cells.

Using both mouse uterine cancer cells and patient-derived tumor models, the researchers showed that RPT04402 could reduce tumor growth and size. Importantly for a drug intended for eventual combination use, the compound did not cause any weight loss or toxicity in the treated animals, an encouraging early signal for tolerability in preclinical models, though such findings in mice and cell systems do not by themselves establish safety or effectiveness in human patients. To our knowledge, this is the first treatment to directly target a driver of high-grade uterine cancers and we're incredibly excited about bringing this treatment to the patients, said Caitlin O'Connor, Research Assistant Professor of Internal Medicine at the University of Michigan.

The team is interested in extending the work beyond gynecologic malignancies to other cancer types and to neurodevelopmental disorders that harbor PP2A mutations, reflecting the enzyme's broad role in human biology. Because PP2A controls many signaling pathways that are frequently disrupted during tumor development and growth, and because its inability to assemble is commonly seen in lung, uterine, prostate and liver cancer, the researchers say the compound RPT04402 can be used to treat a range of human cancers, a possibility that will now need to be tested systematically across tumor types. Both studies are experimental and preclinical, based on cell lines, animal models and patient-derived tumors rather than human trials, so the findings must be validated in clinical testing before any conclusions can be drawn about effectiveness in patients.

The work was supported by the Department of Defense, NIH CMB training grant T32 GM145470, RAPPTA Therapeutics and the National Cancer Institute, including P30 CA046592, F31-CA271463 and T32-CA009676, with additional support from NIH grant P30 CA 046592 35 to the University of Michigan Rogel Cancer Center and Rappta Therapeutics. Several authors disclosed financial relationships with RAPPTA Therapeutics, including personal fees, consulting fees and equity positions, and Narla had an equity stake in RAPPTA Therapeutics and serves as a consultant for the company. The University of Michigan Biomedical Research Core Facilities Vector Core and the BRCF Flow Cytometry Core provided research core support.

The papers cited are A PP2A molecular glue overcomes RAS/MAPK inhibitor resistance in KRAS-mutant non-small cell lung cancer, published in The Journal of Clinical Investigation, and Restoration of PP2A AαB56αC trimer formation by RPT04402 molecular glue in high-grade uterine cancer, published in Science Translational Medicine on October 14, 2026.

Subject of Research: Stabilization of the PP2A tumor suppressor by the molecular glue RPT04402 in preclinical models of KRAS-mutant lung cancer and high-grade uterine cancer

Article Title: ‘Molecular glue’ stabilizes protein that inhibits development of non-small cell lung cancer and uterine cancer

Article References: ‘Molecular glue’ stabilizes protein that inhibits development of non-small cell lung cancer and uterine cancer. Original publication (Bibliographic details unavailable.)

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Keywords: PP2A, molecular glue, RPT04402, non-small cell lung cancer, KRAS, uterine cancer, adagrasib, trametinib, drug resistance, tumor suppressor, preclinical study, University of Michigan