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

PP2A is made up of three proteins that must bind to each other for it to function properly and suppress tumors.

The inability of PP2A to assemble is commonly seen in lung, uterine, prostate and liver cancer.

In two studies, University of Michigan researchers have found that targeting PP2A using a ‘molecular glue’ that helps the protein to retain its structure can help suppress the growth of cancer cells.

Inhibiting tumor growth in non-small cell lung cancer

Lung cancer is the second-most common cancer and the leading cause of cancer death in the United States.

Over 80% 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.

Many gene mutations are associated with non-small cell lung cancer, including the gene KRAS, which is important for cell growth and division and is mutated in 30% of cases.

Patients with tumors that have these mutations have shorter survival times and often become resistant to therapies.

In a study published in The Journal of Clinical Investigation, University of Michigan researchers found that targeting PP2A with the molecular glue RPT04402 can help treat non-small cell lung cancers that have KRAS mutations.

“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 Rogel Cancer Center.

“Although they work well, tumor cells gain resistance after a short period of time.”

Using cell lines of non-small cell lung cancers with KRAS mutations, the team showed that anti-cancer drugs adagrasib and trametinib destabilized PP2A.

This finding could explain why patients eventually become resistant to these therapies. However, when RPT04402 was added, the PP2A complex stabilized and led to cancer cell death.

The researchers confirmed these findings in mouse models and found that the molecular glue caused tumors to shrink.

The combination of adagrasib or trametinib with RPT04402 delayed resistance and increased the treatment effectiveness to over 150 days in mice.

“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 20-30% of all non-small cell lung cancer cases.”

The team plans to start clinical trials in collaboration with Spring Works Therapeutics and Merck.

They also hope to extend this study to include other KRAS-mutant tumors and evaluate whether the drug combination works in pancreatic and colon cancers.

Molecular glue RPT04402 may benefit patients with high-grade uterine cancer

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.

The common treatment methods include surgery and immunotherapy. However, most high-grade uterine cancer patients either do not respond to treatment or their tumors recur.

Researchers have found that recurrent PP2A mutations drive the development of aggressive uterine cancer.

In a study published in Science Translational Medicine, U-M researchers reported that RPT04402 can restore the PP2A’s ability to suppress the growth of uterine cancer cells.

Using both mouse uterine cancer cells and patient-derived tumor models, the team showed that RPT04402 could reduce tumor growth and size. It did not cause any weight loss or toxicity.

They are interested in extending the work to other cancer types and neurodevelopmental disorders that harbor PP2A mutations.

“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.

Additional authors: Brynne Raines, Stephanie Tseng-Rogenski, Amanda C. Dowdican, Irene Peris, Matthew Hinderman, Kaitlin P. Zawacki, Kelsey Barrie, Gabrielle Hodges Onishi, Alexander M. Dymond, Tahra K. Luther, Sydney Musser, Behirda Karaj Majchrowski, J. Chad Brenner, Aqila Ahmed, Derek J. Taylor, Terrance J. Haanen III, Alexander Day, Jiang Hu, Catherine Callahan, Brian Tran, Alexis Harold, Amanda Dowdican, Charles A. Nino, Wei Huang, Daniel Leonard, Brynne Raines, Jaya Sangodkar, Sophie Boock, Varsha Shankar, Miranda Giambi, Silvia Romero-Murillo, Leah Arbitman, Shirish Shenolikar, George Trainor, Frederic Cachoux, Obdulia Rabal, Olga Gherbovet, Laura Fourmois, David L. Brautigan, Analisa V. DiFeo.

Funding/disclosures: The work was supported by the Department of Defense (HT9425-23-LCRP-TRA and HT9425-23-PRCRP-IPA), NIH CMB training grant (T32 GM145470), RAPPTA Therapeutics and National Cancer Institute (P30 CA046592, F31-CA271463 and T32-CA009676), NIH grant P30 CA 046592 35 to University of Michigan Rogel Cancer Center and Rappta Therapeutics.

Michigan Research Core(s): University of Michigan Biomedical Research Core Facilities Vector Core and the BRCF Flow Cytometry Core.

Conflict(s) of Interest: Hodges-Onishi, Zawacki, Hunag and Barrie received personal fees from RAPPTA Therapeutics during the conduct of this work. Trainor has an equity position in RAPPTA Therapeutics. Braugtigan serves as a member of SAB for RAPPTA Therapeutics and has other consulting activities unrelated to this project. Taylor reports receiving consulting fees from RAPPTA Therapeutics. O’Connor reports receiving consulting fees from RAPPTA Therapeutics. Narla had an equity stake in RAPPTA Therapeutics and serves as a consultant for RAPPTA and has served on the SAB for Hera BioLabs.

Paper(s) cited:

“A PP2A molecular glue overcomes RAS/MAPK inhibitor resistance in KRAS-mutant non–small cell lung cancer,” The Journal of Clinical Investigation. DOI: 110.1172/JCI193790

“Restoration of PP2A AαB56αC trimer formation by RPT04402 molecular glue in high-grade uterine cancer,” Science Translational Medicine. DOI: 10.1126/scitranslmed.ady4852.