Scientists at VCU Massey Comprehensive Cancer Center have discovered a promising new combination therapy that could transform treatment for patients with KRAS-mutated non-small cell lung cancer (NSCLC). The breakthrough approach combines sotorasib, an FDA-approved KRAS inhibitor, with FGTI-2734, an experimental drug that prevents cancer cells from developing resistance.
The research, featured on the cover of the Journal of Thoracic Oncology, addresses a critical challenge in precision medicine for lung cancer. While FDA-approved KRAS inhibitors like sotorasib and adagrasib initially offered hope for patients with KRAS G12C mutations—present in approximately 14% of NSCLC cases—most tumors either resist treatment from the start or develop resistance within months.
Mechanism of Action
The novel combination works by targeting multiple aspects of cancer cell survival. Sotorasib directly inhibits the KRAS G12C mutation, while FGTI-2734 blocks wild type RAS membrane localization. This dual approach prevents a cellular process called ERK reactivation, which cancer cells typically use to escape treatment with KRAS inhibitors alone.
"This could be a paradigm shift in how we treat lung cancer," said Said M. Sebti, Ph.D., the study's senior author and associate director for basic research at VCU Massey Comprehensive Cancer Center. "We're hoping to give patients a fighting chance against resistance."
Sebti co-invented FGTI-2734 while at Moffitt Cancer Center, collaborating with Andrew Hamilton, Ph.D., who was at Yale University at the time. The compound was specifically designed to address the resistance mechanisms that limit the effectiveness of current KRAS inhibitor therapies.
Laboratory Success
In laboratory studies using patient-derived tumors, the combination therapy effectively shut down the cancer's ability to develop resistance. When cancer cells were treated with both drugs simultaneously, they were unable to activate alternative survival pathways, ultimately leading to cell death.
The research team included Sebti's lab members Aslamuzzaman Kazi, Ph.D., Hitesh Vasiyani, Ph.D., and Deblina Ghosh, Ph.D., from the Department of Pharmacology and Toxicology at the VCU School of Medicine. Additional collaborators included Jose Trevino, M.D., Rachit Shah, M.D., and Vignesh Vudatha, M.D., from the Department of Surgery, along with Dipankar Bandyopadhyay, Ph.D., from the Department of Biostatistics.
Clinical Implications
The significance of this discovery extends beyond the laboratory. KRAS mutations have long been considered "undruggable" targets, and while recent approvals of KRAS inhibitors represented a major advance, their clinical benefit has been limited by rapid resistance development.
The editor-in-chief of the Journal of Thoracic Oncology authored a breakdown of this research in the March issue, highlighting its potential impact. Additionally, a group of international scientists contributed an editorial detailing their perspective on these findings, further underscoring the importance of this approach in the field of thoracic oncology.
Path to Patient Care
While the results are promising, the researchers acknowledge that laboratory success doesn't always translate directly to clinical benefit. The Massey team is currently working toward securing FDA approval for clinical trials—a crucial step in bringing this innovative therapy to patients.
"Every researcher's dream in this noble field of research is to have a real impact on cancer patients," Sebti emphasized. "This discovery may realize this dream by eventually leading to better outcomes and longer lives for people facing lung cancer."
For patients with KRAS-mutated NSCLC, who often have limited treatment options and poor prognosis, this combination approach could potentially provide a more durable response than current therapies. If successful in clinical trials, the sotorasib and FGTI-2734 combination could represent a significant advancement in precision medicine for lung cancer.
