Glutaminase Inhibition Represents Novel Treatment Strategy in NFE2L2- and KEAP1-Mutated NSCLC

The combination of a glutaminase inhibitor and an mTOR inhibitor could represent a novel strategy for treating patients with NFE2L2- or KEAP1-mutatednon–small cell lung cancer (NSCLC), according to Jonathan Wesley Riess, MD, MS, who added that glutaminase inhibition serves as a method to prevent cancer cells from receiving nutrients and proliferating.

“My co-investigator, Paul K. Paik, MD, of Memorial Sloan Kettering Cancer Center, and I are studying certain types of NSCLC that may be more sensitive to glutaminase inhibition, particularly dual inhibition of glycolysis with the mTOR inhibitor, sapanisertib, and glutaminase inhibition with the glutaminase inhibitor telaglenastat [CB-839],” Riess said.

In an interview with OncLive^® during the 23rd Annual International Lung Cancer Congress^®, Reiss, the director of Thoracic Oncology and an associate professor of medicine at the University of California (UC) Davis, UC Davis Health, discussed a phase 1 trial (NCT04250545) examining the combination of sapanisertib and telaglenastat, and explained why glutaminase inhibition is being investigated as a novel way to treat select patients with NSCLC.

OncLive^®: Could you expand on how glutaminase inhibition could be utilized in NSCLC?

Riess: This is an exciting, novel topic in how to better treat patients with NSCLC. Glutaminase inhibition inhibits the metabolism from glutamine to glutamate. Glutaminase is a mitochondrial enzyme, and then glutamine [converted] to glutamate feeds into the Krebs TCA cycle in terms of providing and feeding the cancer. Glutamine metabolism and glucose via glycolysis are some of the ways cancers can receive nutrients to grow. Glutaminase inhibition helps to prevent that. But there are multiple other ways that cancer cells can get nutrients and survive.

Could you expand on the rationale of the phase 1 trial examining the combination of a glutaminase inhibitor and an mTOR inhibitor?

There are cases of NFE2L2-mutant and KEAP1-mutant NSCLC which affect the NRF2 pathway. NRF2 is encoded by NFE2L2, and KEAP1 is its negative regulator. In patients with these mutations, which comprise about a quarter of all squamous NSCLC and about a quarter of KRAS-mutant NSCLC, there is preclinical evidence that those lung cancers may be particularly sensitive to this dual inhibition.

We are studying [the combination of sapanisertib and telaglenastat] in an early phase 1 trial sponsored by the National Cancer Institute, which is a dose-escalation study with expansion cohorts probing for preliminary efficacy in KRAS/KEAP1–co-mutant NSCLC and squamous NFE2L2-mutant NSCLC. Additional preclinical data from the David Shackelford Lab at UCLA showed that one of the reasons mTOR inhibition was unsuccessful as a single agent in squamous NSCLC was that selection for these NFE2L2 and KEAP1 mutations were not done. Additionally, cancers can switch to glutaminolysis, using that glutamine to glutamate pathway to feed into the Krebs TCA cycle when glycolysis is blocked via mTOR inhibition. By targeting both with the mTOR inhibitor and glutaminase inhibitor, there’s good potential additional efficacy, and that’s what we’re looking for in this clinical trial.

What is the potential significance of biomarker testing to determine the best responders to this therapy? What mutations stand out as potential biomarkers?

Mutations that may affect the NRF2 pathway, such as NFE2L2 and KEAP1, [are notable]. NFE2L2 is the gene that encodes for NRF2. It’s mutated in about a quarter of all squamous lung cancers in combination with KEAP1, and about a quarter of all KRAS-mutant NSCLC. KEAP1 is its negative regulator, and it is more mutated in KRAS-mutant NSCLC. NFE2L2 is slightly more [mutated] in squamous NSCLC. We think those [mutations] are potentially actionable via glutaminase inhibition, particularly in combination with mTOR inhibition.

How may glutaminase inhibition build on the current standard of care in this population?

In terms of the current standard of care, there’s nothing currently actionable with targeted therapies for NFE2L2-mutant or KRAS/KEAP1–co-mutated NSCLC. In terms of building on the standard of care, there was a clinical trial called the [phase 2] KEAPSAKE trial [NCT04265534] with chemotherapy and telaglenastat, the glutaminase inhibitor, in KEAP1-mutated, nonsquamous NSCLC. Unfortunately, there was a press release in November 2021 that the randomized trial was negative. We haven’t seen the published data yet.

In terms of the future, looking for combinations with mTOR inhibitors and selecting for KRAS/KEAP1 mutations or KEAP1/NFE2L2-mutated squamous NSCLC is the way forward to refine that biomarker selection based upon their dependence on glutamine metabolism, at least [from what was observed] in preclinical modeling.

What is the importance of studying these agents in lung cancer?

In our phase 1 study, we are probing for those NFE2L2- and KEAP1-mutated cohorts to look for efficacy, to see if by dual targeting of glycolysis and glutaminolysis we could have increased clinical activity in both squamous and KRAS–co-mutated NSCLC, which is an area of unmet need.

Moreover, there’s a signal that KRAS/KEAP1–co-mutant NSCLC may potentially not be as beneficial to direct KRAS G12C inhibitors, such as sotorasib [Lumakras]. We still need further data on that. Combination strategies and combining [glutaminase inhibitors] with direct RAS inhibitors may be something to look for in the future.