Researchers at UT Southwestern Harold C. Simmons Comprehensive Cancer Centre led a recent clinical trial that found selinexor, a drug already FDA-approved for treating multiple myeloma and lymphoma, can effectively shrink tumours in non-small cell lung cancer (NSCLC) patients with KRAS mutations. The findings, published in Clinical Cancer Research, suggest a potential breakthrough for one of the most difficult subtypes of lung cancer. 

"This novel treatment appears promising for one of the most common and difficult-to-treat forms of lung cancer," said Dr. David E. Gerber, Professor of Internal Medicine and the study's co-leader. He emphasized the importance of the findings, citing limited therapy choices for individuals with KRAS-mutated lung tumors.

According to the American Cancer Society, lung cancer continues to be the largest cause of cancer-related fatalities in the United States, with over 234,000 new cases projected this year. The American Cancer Society classifies approximately 85% of these cases as NSCLC, and approximately 25% of these cases have mutations in the KRAS gene, a prevalent driver in a variety of cancer types, including colorectal and pancreatic cancers.

Despite years of research, KRAS-mutated tumours have proven notoriously tough to treat. Recently approved medications such as sotorasib (2021) and adagrasib (2022) have offered some hope, although their efficacy is limited to certain KRAS mutations and typically lasts just six months. 

"Effective treatments for KRAS mutant lung cancer remain a major unmet clinical need," stated Dr. Mitchell S. von Itzstein, the study's first author and an Assistant Professor of Internal Medicine at UT Southwestern. 

UT Southwestern researchers discovered some years ago that selinexor, a nuclear export inhibitor, specifically killed cancer cells carrying KRAS mutations in preclinical studies. To expand on these findings, Drs. Gerber and von Itzstein undertook a clinical investigation involving 40 NSCLC patients with varied KRAS mutations. 

All individuals had advanced cancer and had undergone numerous previous treatments, including chemotherapy, immunotherapy, or targeted therapies, but their tumours persisted in growing. The trial administered a weekly oral dose of selinexor to patients, followed by docetaxel, a chemotherapy medication routinely used in NSCLC.

The trial yielded optimistic results, as the combination treatment successfully managed cancer in approximately 80% of cases, a success rate significantly higher than that of docetaxel alone. Surprisingly, selinexor proved effective against all forms of KRAS mutations. 

However, adverse effects were widespread, including nausea, fatigue, diarrhea, and neutropenia (a decrease in white blood cells).  Despite these side effects, the majority of individuals found that the treatment's benefits outweighed the risks. Tumours that did not respond to treatment were more likely to have inactivating mutations in the tumour-suppressing gene TP53. 

Interestingly, the researchers discovered data indicating that selinexor may have anti-tumour effects on its own, even without the addition of docetaxel. This paves the way for further investigation into the use of selinexor alone in KRAS-mutated NSCLC.

"Our results suggest that selinexor could be a useful addition to our toolbox for treating lung cancer and may offer hope for other cancers with KRAS mutations," said Dr. Gerber, who holds the David Bruton, Jr. Professorship in Clinical Cancer Research. 

The trial's findings not only give hope to NSCLC patients, but they also offer the possibility of employing selinexor to treat other KRAS-driven malignancies, such as colorectal and pancreatic cancer. 

As researchers prepare additional trials to verify selinexor's solo efficacy, the preliminary findings underscore the promise for a novel method to combat one of the deadliest and most treatment-resistant cancer types.

This study emphasizes the need for ongoing cancer therapy innovation and collaboration among researchers, doctors, and pharmaceutical corporations to address unmet medical needs.