Researchers at the University of Michigan have developed a promising new approach to treat difficult lung cancers, specifically targeting those with mutations in the KRAS gene. This innovative strategy combines a novel molecular glue with existing KRAS inhibitors, successfully delaying treatment resistance and resulting in significant tumor shrinkage in laboratory models.
Lung cancer remains the leading cause of cancer-related deaths in the United States and ranks as the second-most common cancer worldwide. Over 80% of lung cancer cases are classified as non-small cell lung cancers (NSCLC), characterized by larger tumor cells that typically grow at a slower pace than small cell lung cancers. Despite advancements in treatment, patients with NSCLC, particularly those with KRAS mutations, often experience poor outcomes and limited therapeutic options. Approximately 30% of NSCLC cases involve mutations in the KRAS gene, leading to reduced survival rates and resistance to current treatments.
To address the challenges posed by these mutations, the University of Michigan research team focused on a protein complex known as protein phosphatase 2A (PP2A). This complex plays a crucial role in inhibiting lung cancer development and is composed of three proteins that must be assembled correctly to function. Disruption of this assembly is frequently observed in various cancers, including lung, prostate, and liver cancers. Researchers sought to determine if stabilizing the PP2A complex could suppress tumor growth effectively.
Current FDA-approved treatments targeting KRAS, such as adagrasib (Krazati) and trametinib (Mekinist), have been used for pancreatic, colon, and lung cancers. However, these treatments often lead to resistance in tumor cells after a relatively short period. Dr. Goutham Narla, Louis Newburgh Research Professor of Internal Medicine and member of the Rogel Cancer Center, stated, “Although they work well, tumor cells gain resistance after a short period of time.”
In their study, published in The Journal of Clinical Investigation, the researchers discovered that both adagrasib and trametinib destabilized the PP2A complex in KRAS-mutant NSCLC cell lines, which may explain the development of resistance. They introduced a novel molecular glue, RPT04402, designed to stabilize PP2A. When this molecular glue was incorporated into the treatment regimen, it restored PP2A function and induced cancer cell death.
In preclinical mouse models, the combination of RPT04402 and existing treatments not only reduced tumor size but also postponed the onset of resistance, extending treatment efficacy to over 150 days. Additional experiments demonstrated that combining RPT04402 with RAS/MAPK inhibitors slowed the proliferation of cancer cells and enhanced programmed cell death, or apoptosis, in both commercial and patient-derived models. The research indicates that restoring PP2A activity could counteract the resistance mechanisms driven by disrupted feedback in KRAS-mutant tumors.
Despite the encouraging results, Dr. Narla cautions that this treatment approach may not be suitable for all NSCLC cases, as the study primarily focuses on the subset of patients with KRAS mutations, which account for about 20% to 30% of all NSCLC cases. The research team plans to initiate clinical trials in collaboration with Spring Works Therapeutics and Merck, with aspirations to extend the applicability of this approach to KRAS-mutant pancreatic and colon cancers.
This groundbreaking study suggests a potential new paradigm in cancer treatment by combining molecular glues that stabilize tumor-suppressing proteins with targeted inhibitors. If successful in human patients, this strategy could offer a vital new option for those battling KRAS-mutant NSCLC, a patient population currently facing limited treatment success and often, short-lived results.
