Lung cancer is the second-most common cancer and the leading cause of cancer death in the United States. Over 80% of lung cancers are non-small cell lung cancers, in which tumor cells are larger and grow more slowly than those in small cell lung cancer. Many gene mutations are associated with non-small cell lung cancer, including the K-Ras gene, which is important for cell growth and division and is mutated in 30% of cases. Patients with tumors that have these mutations have shorter survival times and often become resistant to therapies. In a study now published in The Journal of Clinical Investigation, University of Michigan researchers found a new protein target and developed a drug to treat non-small cell lung cancers that have K-Ras mutations.
The current study focused on protein phosphatase 2A, which has been shown to inhibit lung cancer development. PP2A is made up of three proteins that must bind to each other for the protein to function properly. It controls numerous fundamental processes, including cell cycle progression (mitosis), growth, differentiation and apoptosis. The B subunit guides the complex to specific proteins, influencing signaling pathways (e.g., affecting Tau, Akt, p53, c-Myc). Moreover, viruses like SV40 target PP2A to promote cell transformation, highlighting its importance in cell cycle control. The inability of PP2A to assemble is commonly seen in lung, prostate and liver cancer, which led the researchers to ask whether stabilizing the complex can help inhibit tumor growth.
Using cell lines of non-small cell lung cancers with KRAS mutations, the team showed that anti-cancer drugs adagrasib and trametinib destabilized PP2A. This finding could explain why patients eventually become resistant to these therapies. The most likely mechanism behind this could be that the simultaneous inhibition of mutant Ras (adagrasib) and protein kinase MEK upstream to MAP-kinase ERK (trametinib), removes regulation of this kinase on PP2A itself. However, when a molecular glue called RPT04402 was added, PP2A was stabilized and led to cancer cell death. The researchers confirmed these findings in mouse models and found combination of adagrasib or trametinib with RPT04402 delayed resistance and increased the treatment effectiveness to over 150 days.
RPT04402 (now SW-3431) is a novel small molecule drug candidate developed by Rappta Therapeutics and licensed to SpringWorks Therapeutics, with plans for an Investigational New Drug (IND) filing by late 2025 to treat cancers like uterine cancer and potentially overcome resistance to other therapies. The team plans to start clinical trials in the near future in collaboration with Spring Works Therapeutics and Merck. They also hope to extend this study to include other KRAS-mutant tumors and evaluate whether the drug combination works in pancreatic and colon cancers.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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