A drug approved for multiple myeloma and lymphoma has shown remarkable potential in shrinking tumors in non-small cell lung cancer (NSCLC) with KRAS mutations. Research led by UT Southwestern Harold C. Simmons Comprehensive Cancer Center highlights a breakthrough in targeted cancer treatment. These findings, published in Clinical Cancer Research, pave the way for more effective therapies for a challenging cancer subtype.
KRAS Mutations: A Persistent Challenge
Lung cancer remains one of the most diagnosed cancers in the U.S., with over 234,000 cases annually. NSCLC accounts for 85% of these cases, and approximately 25% involve KRAS mutations. These mutations are common across multiple cancers, including colorectal and pancreatic cancers. Despite their prevalence, treatments targeting KRAS mutations have been limited.
Until recently, only two FDA-approved drugs, sotorasib and adagrasib, addressed KRAS mutations in NSCLC. However, these therapies provide modest benefits and apply to only 30% of specific KRAS mutation cases, highlighting an unmet need for more effective treatments.
Selinexor: A Promising Approach
Researchers identified selinexor, a nuclear export inhibitor, as a potential treatment for NSCLC with KRAS mutations. In preclinical trials, the drug killed cancer cells and reduced tumor size in models with these mutations, showing no impact on tumors without them.
To validate these results, a clinical trial involving 40 NSCLC patients was conducted. These individuals had undergone various treatments, including chemotherapy and immunotherapy, but their cancers continued to progress. Patients received weekly oral doses of selinexor, followed by docetaxel, a chemotherapy agent.
Encouraging Results
The combination treatment effectively controlled cancer in about 80% of cases—significantly higher than docetaxel alone. Importantly, selinexor showed efficacy across all KRAS mutation types. The study also revealed that tumors resistant to treatment often had mutations in TP53, a tumor-suppressing gene.
Selinexor demonstrated independent anti-tumor activity before introducing chemotherapy. This finding has inspired researchers to explore its standalone efficacy in future trials.
Managing Side Effects
Like many cancer treatments, the combination therapy caused side effects, including nausea, fatigue, diarrhea, and neutropenia (low white blood cell counts). Despite these challenges, the therapy’s benefits in controlling aggressive cancers outweighed its risks.
Expanding the Treatment Toolbox
The study’s co-leader, Dr. David Gerber, emphasized the significance of these findings. “Selinexor could be a valuable addition to our arsenal for treating KRAS-mutated lung cancer. It also opens the door for exploring its use in other cancers with similar genetic profiles,” he said.
Future Implications
This discovery brings hope to patients battling hard-to-treat cancers. By targeting a broader range of KRAS mutations, selinexor could address longstanding gaps in cancer care. Ongoing research aims to optimize its use and evaluate its potential in treating other malignancies.
This breakthrough highlights the power of repurposing existing drugs to tackle complex health challenges, offering renewed hope to patients and their families.
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