'Molecular glue' stabilizes protein that inhibits development of 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 a new protein target and developed a drug to 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.”

The current study focused on protein phosphatase 2A, which has been shown to inhibit lung cancer development.

PP2A is made up of three proteins that must bind to each other for the protein to function properly.

There are several FDA-approved drugs that target KRAS in pancreatic, colon and lung cancer. Although they work well, tumor cells gain resistance after a short period of time.” 

-Goutham Narla, M.D., Ph.D.

The inability of PP2A to assemble is commonly seen in lung, prostate and liver cancer, which led the researchers to ask whether stabilizing the complex can help inhibit tumor growth.

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 a molecular glue called 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 20-30% of all small cell lung cancer cases.”

The team plans to start clinical trials in the near future 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.

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 and Caitlin M. O’Connor.

Funding/disclosures: The work was supported by the Department of Defense (HT9425-23-LCRP-TRA), NIH CMB training grant (T32 GM145470), RAPPTA Therapeutics and National Cancer Institute (P30 CA046592).

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

Paper cited: “A PP2A molecular glue overcomes RAS/MAPK inhibitor resistance in KRAS-mutant non–small cell lung cancer,” The Journal of Clinical Investigation. DOI: 10.1172/JCI193790

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