A recent study has identified a novel protein target for combating KRAS-driven non-small cell lung cancer
Lung cancer ranks as the second most prevalent cancer and is the foremost cause of cancer-related fatalities in the United States.
Non-small cell lung cancers account for over 80% of lung cancer cases, characterized by larger tumor cells that proliferate at a slower rate compared to small cell lung cancer.
Numerous gene mutations are linked to non-small cell lung cancer, notably the KRAS gene, which plays a crucial role in cellular growth and division and is mutated in approximately 30% of instances.
Patients whose tumors exhibit these mutations tend to have reduced survival rates and frequently develop resistance to treatments.
In a publication featured in The Journal of Clinical Investigation, researchers from the University of Michigan discovered a new protein target and formulated a drug aimed at treating non-small cell lung cancers with KRAS mutations.
“There are multiple FDA-approved medications that target KRAS in pancreatic, colon, and lung cancers,” stated Goutham Narla, the Louis Newburgh Research Professor of Internal Medicine and a member of the Rogel Cancer Center.
“While these drugs are effective, tumor cells often acquire resistance after a brief duration.” The present study concentrated on protein phosphatase 2A, which has demonstrated the ability to impede the progression of lung cancer. PP2A consists of three proteins that must interact with one another for the protein to operate effectively.
The inability of PP2A to assemble is frequently observed in lung, prostate, and liver cancers, prompting researchers to investigate whether stabilizing the complex could aid in inhibiting tumor growth.
Utilizing cell lines from non-small cell lung cancers with KRAS mutations, the research team demonstrated that the anti-cancer medications adagrasib and trametinib led to the destabilization of PP2A.
This discovery may elucidate the reason why patients ultimately develop resistance to these treatments. Nevertheless, the introduction of a molecular glue known as RPT04402 resulted in the stabilization of the PP2A complex, which subsequently induced cancer cell death.
The researchers validated these results in mouse models, observing that the molecular glue contributed to tumor reduction.
The combination of adagrasib or trametinib with RPT04402 not only delayed resistance but also enhanced treatment efficacy to over 150 days in mice.
“While we examined various cell lines and animal models, we remain uncertain if this combination will be effective in all instances of non-small cell lung cancer,” Narla stated.
“Our results account for 20-30% of all small cell lung cancer cases.”
The team intends to initiate clinical trials soon in partnership with Spring Works Therapeutics and Merck.
They also aspire to broaden this research to encompass other KRAS-mutant tumors and assess the efficacy of the drug combination in pancreatic and colon cancers.