Research from the University of Michigan has uncovered a promising new approach to treating non-small cell lung cancer (NSCLC), a disease responsible for the majority of lung cancer cases and deaths worldwide. Scientists have identified a molecular glue, RPT04402, that stabilizes a crucial protein complex, potentially overcoming resistance to existing therapies for cancers driven by mutations in the KRAS gene.
Lung cancer is the second most prevalent cancer and the leading cause of cancer mortality in the United States. Of all lung cancer diagnoses, over 80% are classified as non-small cell lung cancers, known for their larger tumor cells that grow at a slower rate compared to small cell lung cancer. Notably, mutations in the KRAS gene—critical for cell growth—are implicated in approximately 30% of NSCLC cases. Patients with these mutations often face shorter survival times and develop resistance to treatment options.
In a study published in the Journal of Clinical Investigation, researchers led by Goutham Narla, a professor at the University of Michigan’s Rogel Cancer Center, explored a new therapeutic target focused on protein phosphatase 2A (PP2A). This protein has demonstrated an ability to inhibit the development of lung cancer. Researchers discovered that the assembly of PP2A, which consists of three interdependent proteins, is often disrupted in lung, prostate, and liver cancers.
The study indicated that when tested against non-small cell lung cancer cell lines harboring KRAS mutations, two existing anti-cancer drugs, adagrasib and trametinib, destabilized the PP2A complex. This destabilization may explain the frequent resistance observed in patients undergoing treatment. By introducing RPT04402, the PP2A complex was stabilized, leading to effective cancer cell death. Remarkably, this stabilization resulted in significant tumor shrinkage in mouse models.
Combining RPT04402 with either adagrasib or trametinib delayed the onset of treatment resistance and enhanced therapeutic effectiveness, extending the duration of effective treatment to over 150 days in the tested mice. Despite these promising results, Narla cautioned that the findings may not universally apply to all cases of non-small cell lung cancer, as they represent only about 20-30% of all instances.
Looking ahead, the research team plans to initiate clinical trials in collaboration with Spring Works Therapeutics and Merck. Their goal is to expand this study to encompass other cancers driven by KRAS mutations, including pancreatic and colon cancers. As the research progresses, the implications for improved treatment protocols could have a significant impact on patient outcomes in these challenging cancer types.
The findings from this study underscore the ongoing need for innovative strategies in cancer treatment, particularly for patients facing the challenges of drug resistance.
