Dr. Rizvi on the Rationale to Evaluate Telaglenastat in KEAP1/NRF2-Mutant NSCLC
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Naiyer A. Rizvi, MD, discusses the rationale to evaluate the investigational glutaminase inhibitor telaglenastat in patients with non–small cell lung cancer who harbor KEAP1 or NRF2 mutations.
Naiyer A. Rizvi, MD, Price Family Professor of Medicine, director, Thoracic Oncology, co-director, Cancer Immunotherapy, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, research director, Price Family Comprehensive Center for Chest Care, NewYork-Presbyterian Hospital, discusses the rationale to evaluate the investigational glutaminase inhibitor telaglenastat (CB-839) in patients with non–small cell lung cancer (NSCLC) who harbor KEAP1 or NRF2 mutations.
KEAP1-mutant tumors are thought to be highly proliferative and largely dependent on glutamine to complete anabolic metabolism, says Rizvi. Moreover, fast-growing tumors have significant anabolic metabolism requirements. These requirements can be dependent on glucose or glutamine, depending on the body’s anabolic state.
Glutamine is metabolized to glutamate for DNA protein synthesis, Rizvi explains. Additionally, glutamine is converted to glutathione, which can protect cancer cells from oxidative stress, says Rizvi.
As such, preclinical models with telaglenastat in patients with KEAP1/NRF2-mutant NSCLC have shown that inhibiting glutamine metabolism with an agent such as telaglenastat can increase the oxidative stress within the cancer cells. Giving telaglenastat in combination with standard of care options, such as pembrolizumab (Keytruda), carboplatin, and pemetrexed, may elicit improved tumor destruction, concludes Rizvi.
