Breakthrough drug combination targets KRAS mutation in lung cancer

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A breakthrough in lung cancer treatment may be on the horizon. Scientists at VCU Massey Comprehensive Cancer Center have uncovered a powerful combination therapy leveraging sotorasib-an FDA-approved drug in the market-and an experimental drug called FGTI-2734, which could make precision medicine more effective for patients with a highly resistant form of lung cancer. The study, featured on the cover of the Journal of Thoracic Oncology, reveals a potential game-changer for patients battling tumors with the KRAS G12C mutation-a driver in about 14% of non-small cell lung cancers.
FDA-approved drugs sotorasib and adagrasib have given new hope to some patients by targeting this KRAS G12C mutation, but the majority of tumors fight back, either resisting treatment from the start or relapsing within months. That's where Massey's latest discovery, led by Said M. Sebti, Ph.D., the cancer center's associate director for basic research and Lacy Family Chair in Cancer Research, offers a potential new solution.

By combining sotorasib with FGTI-2734, co-invented by Sebti while he was at Moffitt Cancer Center and Andrew Hamilton, Ph.D., while he was at Yale University, Massey researchers shut down the cancer's ability to develop resistance. FGTI-2734 blocks cancer cells' wild type RAS membrane localization, prohibiting a cellular process called ERK reactivation, where ERK belongs to a family of enzymes that regulates communication within cells. Cancer cells use ERK reactivation to escape sotorasib treatment. The result: cancer cells panic and die.

While these results were seen in lab studies using patient-derived tumors, the Massey team is working toward securing FDA approval for clinical trials-a crucial step toward bringing this innovation to patients.

"Every researcher's dream in this noble field of research is to have a real impact on cancer patients," added Sebti. "This discovery may realize this dream by eventually leading to better outcomes and longer lives for people facing lung cancer."

The editor-in-chief of the Journal of Thoracic Oncology authored a breakdown of this research in the March issue of the journal, and a group of international scientists wrote an accompanying editorial detailing their perspective on these findings.

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