University of Michigan researchers have found a way to use a “molecular glue” to stabilize a tumor-suppressing protein and shrink drug-resistant lung tumors in mice. The approach could help extend the effectiveness of existing treatments for KRAS-mutant cancers.
A new “molecular glue” strategy from University of Michigan scientists could help outsmart one of lung cancer’s toughest tricks: its ability to become resistant to treatment.
In a study published in The Journal of Clinical Investigation, the researchers identified a new protein target and developed a drug that, in combination with existing therapies, shrank tumors and delayed resistance in models of non-small cell lung cancer with KRAS mutations.
Lung cancer is the second-most common cancer and the leading cause of cancer death in the United States. More than 80% of lung cancers are non-small cell lung cancers, and many of these tumors carry mutations in a gene called KRAS, which helps control cell growth and division. KRAS mutations are found in about 30% of non-small cell lung cancer cases and are linked to shorter survival and resistance to therapy.
Over the past several years, new drugs have been approved that directly target KRAS in pancreatic, colon and lung cancers.
“There are several FDA-approved drugs that target KRAS in pancreatic, colon and lung cancer,” senior author Goutham Narla, the Louis Newburgh Research Professor of Internal Medicine and a member of Rogel Cancer Center, said in a news release. “Although they work well, tumor cells gain resistance after a short period of time.”
The Michigan team set out to understand why that resistance develops and how to prevent it.
Instead of focusing only on KRAS itself, the researchers turned to a different protein complex called protein phosphatase 2A, or PP2A. PP2A acts as a tumor suppressor, helping to inhibit lung cancer development. It is made up of three separate proteins that must fit together correctly for the complex to function.
In many cancers, including lung, prostate and liver, PP2A does not assemble properly. That breakdown removes an important brake on tumor growth. The Michigan group asked a simple but powerful question: if they could stabilize PP2A and help it assemble, could they restore its cancer-fighting power?
Using cell lines of non-small cell lung cancers with KRAS mutations, the team tested two anti-cancer drugs that are already used in patients, adagrasib and trametinib. They found that these drugs destabilized PP2A. That destabilization, the researchers suggest, may help explain why tumors that initially respond to treatment eventually become resistant.
The breakthrough came when they added a compound called RPT04402, described as a molecular glue. Rather than attacking cancer cells directly, this glue helps hold the three parts of PP2A together, stabilizing the complex.
When RPT04402 was added to the cancer cells along with adagrasib or trametinib, PP2A stayed intact and its tumor-suppressing activity kicked in. The result was cancer cell death in the lab.
The team then moved to mouse models of KRAS-mutant non-small cell lung cancer to see if the same effect would hold up in living organisms. It did. The molecular glue caused tumors to shrink, and when combined with adagrasib or trametinib, it delayed the onset of resistance and extended the effectiveness of treatment to more than 150 days in mice.
Those findings suggest that shoring up the body’s own tumor-suppressing machinery could be a powerful way to boost existing targeted therapies and make them work longer.
The researchers emphasize that their work so far has been in cell lines and animals, not in patients. They also note that the approach is unlikely to be a one-size-fits-all solution for every person with non-small cell lung cancer. According to the study, the findings represent a subset of cases within KRAS-mutant disease.
“Our findings represent 20-30% of all small cell lung cancer cases,” added Narla.
Still, the potential impact is significant. KRAS mutations are common across several major cancers, and resistance to targeted drugs remains a major challenge in oncology. By focusing on PP2A and using a molecular glue to stabilize it, the Michigan team has opened a new path for combination therapies that might keep tumors in check for longer.
Next, the researchers plan to move this strategy toward the clinic. They intend to launch clinical trials in collaboration with SpringWorks Therapeutics and Merck to test whether combining RPT04402 with existing drugs can safely benefit patients with KRAS-mutant non-small cell lung cancer.
They also hope to expand their work beyond lung cancer, exploring whether the same drug combination could help treat KRAS-mutant pancreatic and colon cancers, where resistance to targeted therapies is also a pressing problem.
If future trials are successful, the molecular glue approach could mark a shift in how doctors think about cancer treatment: not just blocking cancer-driving genes, but also reinforcing the body’s natural tumor suppressors so that therapies stay effective longer.
Source: Michigan Medicine