Study finds a new protein target against KRAS-driven 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.

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

"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.

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.

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.

Source:

Michigan Medicine - University of Michigan

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