New Drug Strategy Shows Promise Against KRAS-Mutant Lung Cancer

Researchers at the University of Michigan have unveiled a promising new approach to combat lung cancer, specifically targeting KRAS mutations that often lead to therapy resistance. By combining a molecular glue with existing KRAS inhibitors, this innovative strategy has demonstrated significant tumor shrinkage in laboratory models, potentially extending the effectiveness of treatments for patients with this challenging form of cancer.

Lung cancer remains the leading cause of cancer-related deaths in the United States and ranks as the second-most common cancer globally. Within this category, over 80% of cases are classified as non-small cell lung cancers (NSCLC), characterized by larger tumor cells that typically grow more slowly than their small cell counterparts. Despite advances in treatment, individuals with NSCLC harboring specific genetic mutations, particularly in the KRAS gene, often face poor prognoses and limited options.

Approximately 30% of NSCLC cases involve mutations in the KRAS gene, which is crucial for cell growth and division. These mutations often lead to shorter survival times and increased resistance to current therapies. To address this issue, the research team at the University of Michigan identified a new protein target and developed a novel drug aimed at KRAS-mutant NSCLC. The findings were published in The Journal of Clinical Investigation.

Exploring the Role of PP2A

The study highlights the significance of protein phosphatase 2A (PP2A), a protein complex known to inhibit lung cancer progression. PP2A consists of three proteins that must assemble correctly to function. Disruption of this assembly is commonly observed in various cancers, including lung, prostate, and liver cancers. Researchers aimed to determine whether stabilizing the PP2A complex could suppress tumor growth.

Current FDA-approved drugs such as adagrasib (Krazati; Mirati Therapeutics) and trametinib (Mekinist; Novartis) target KRAS in pancreatic, colon, and lung cancers. Despite their effectiveness, tumor cells often develop resistance relatively quickly. “There are several FDA-approved drugs that target KRAS in pancreatic, colon, and lung cancer. Although they work well, tumor cells gain resistance after a short period,” said Goutham Narla, MD, PhD, Louis Newburgh Research Professor of Internal Medicine at the Rogel Cancer Center.

The team discovered that both adagrasib and trametinib destabilized the PP2A complex in KRAS-mutant NSCLC cell lines. This finding may explain the development of resistance observed in patients. Following this discovery, they tested a novel molecular glue, RPT04402, designed to stabilize PP2A. When added to the treatment regimen, RPT04402 not only restored PP2A function but also triggered cancer cell death.

In mouse models, the combination of RPT04402 and existing therapies resulted in significant tumor shrinkage and delayed the onset of resistance, extending treatment effectiveness to over 150 days. Additional experiments demonstrated that combining RPT04402 with RAS/MAPK inhibitors slowed cancer cell proliferation and enhanced apoptosis in both commercial cell lines and patient-derived models.

Future Directions and Clinical Trials

While the results are promising, Narla cautions that this combination may not be a universal solution for all NSCLC cases. The study specifically focuses on KRAS mutations, which account for approximately 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 of eventually applying 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 critical new treatment option for individuals with KRAS-mutant NSCLC, a group that currently has limited and often short-lived treatment successes.