‘Molecular glue’ stabilises protein that inhibits development of non-small cell lung cancer and uterine cancer
Protein phosphatase 2A plays a central role in controlling many cell signalling pathways, which are frequently disrupted during tumour development and growth.
PP2A is made up of three proteins that must bind to each other for it to function properly and suppress tumours.
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 tumour 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 tumours 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 Centre.
“Although they work well, tumour 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 destabilised PP2A.
This finding could explain why patients eventually become resistant to these therapies.
However, when RPT04402 was added, the PP2A complex stabilised and led to cancer cell death.
The researchers confirmed these findings in mouse models and found that the molecular glue caused tumours 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 tumours 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 gynaecological malignancy.
The common treatment methods include surgery and immunotherapy.
However, most high-grade uterine cancer patients either do not respond to treatment or their tumours 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 tumour models, the team showed that RPT04402 could reduce tumour 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 harbour 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.