Lung cancer remains a leading health challenge, being the second-most common cancer and the foremost cause of cancer-related deaths in the United States. Among the various types, over 80% are classified as non-small cell lung cancers (NSCLC), characterized by larger tumor cells that grow at a slower pace compared to small cell lung cancer. A significant aspect of NSCLC is the presence of gene mutations, particularly in the KRAS gene, which is mutated in approximately 30% of cases. These mutations often lead to shorter survival times for patients and contribute to resistance against therapeutic interventions.
Recent findings from researchers at the University of Michigan, published in The Journal of Clinical Investigation, highlight a promising strategy for treating NSCLC associated with KRAS mutations. The study, led by Goutham Narla, Louis Newburgh Research Professor of Internal Medicine and a member of the Rogel Cancer Center, identifies a new protein target that could enhance treatment efficacy. Narla noted that while several FDA-approved drugs currently target KRAS in various cancers, including pancreatic and colon cancers, tumor cells often develop resistance shortly after treatment initiation.
Understanding the Role of PP2A in Lung Cancer
The focus of this investigation centered on protein phosphatase 2A (PP2A), which has demonstrated an ability to inhibit the development of lung cancer. PP2A consists of three proteins that must bind together to function effectively. Disruptions in this assembly are frequently observed in lung, prostate, and liver cancers, prompting researchers to explore whether stabilizing this protein complex could impede tumor growth.
Using cell lines derived from non-small cell lung cancers with KRAS mutations, the research team discovered that existing anti-cancer drugs, such as adagrasib and trametinib, cause destabilization of PP2A. This destabilization may elucidate why patients often experience resistance to these therapies. However, the introduction of a molecular glue, identified as RPT04402, successfully stabilized the PP2A complex, leading to significant cancer cell death.
Encouraging Results and Future Directions
The researchers confirmed these findings through experiments with mouse models, where the application of RPT04402 led to a reduction in tumor size. Furthermore, combining RPT04402 with either adagrasib or trametinib not only delayed the onset of resistance but also extended the treatment’s effectiveness to over 150 days in these models. Narla emphasized that while the study tested various cell lines and animal models, the applicability of this combination treatment across all cases of non-small cell lung cancer remains uncertain, as it currently represents only 20-30% of NSCLC cases.
Looking ahead, the research team plans to initiate clinical trials in collaboration with Spring Works Therapeutics and Merck. They also aim to broaden the scope of their investigation to include other tumors with KRAS mutations, particularly in pancreatic and colon cancers, offering hope for more effective treatment options in the future.
The findings underscore a significant advancement in the treatment landscape for non-small cell lung cancer, particularly for patients with challenging KRAS mutations. As research progresses, the prospect of overcoming resistance to current therapies could reshape the standard of care in oncology.
