Role of glutaminase in lung cancer

The researchers have discovered cancer and immune cells rely on the same energy sources from our body to thrive, which could trigger a fundamental rethink of treatment options for some lung cancer patients.

The study found a method currently used to treat an aggressive form of lung cancer in clinical trials inadvertently prevents immune cells from protecting the body against the disease.

Mapping the ‘energy fingerprints’ involved, the study indicates treatments that aim to suppress tumor growth while simultaneously boosting the immune system may be counterproductive.

  • Research finds a combination treatment used for lung adenocarcinoma – a common form of lung cancer – may not be beneficial to patients, despite entering clinical trials. 

  • The team discovered the combined use of a glutaminase inhibitor and immunotherapy suppressed the activity of both cancer and T cells. T cells are crucial in the body’s fight against diseases like cancer.

  • Findings could lead to a fundamental change in approach to lung cancer treatments, highlighting the importance of evaluating combination treatments in sophisticated preclinical models before human trials.

Immunotherapy is an emerging form of cancer treatment that boosts the immune system to supercharge T cells – immune cells critical to the body’s ability to fight cancer – and is currently being used to treat many lung adenocarcinoma patients.

Tumors usually rely on an energy source known as glutamate to grow and survive. Drugs known as glutaminase inhibitors have been developed to suppress the growth of cancerous tumors by blocking glutamate from releasing its energy. 

A combined therapy currently in clinical trials involves a glutaminase inhibitor and immunotherapy, in an approach researchers hoped would provide dual benefits, by blocking tumor growth and supercharging T cells. 

But a new study provides a fundamental rethink on whether this combined treatment is beneficial. The research is published in Cell Metabolism.

Lead author, said testing the glutaminase inhibitor on preclinical models delivered surprising results.

“We found the drug was not only blocking the activity of the tumor but also the activity of T cells, which are critical to the body’s fight in killing these tumours,” the lead said.

“Immunotherapy works by enhancing the activity of T cells. Our findings show the glutaminase inhibitor counteracts the benefits of immunotherapy, because the drug suppresses T cells from functioning and protecting our body.”

Researchers say the findings are critical, given patients in clinical trials are currently receiving this combined immunotherapy and glutaminase inhibition treatment.
“These immune cells rely on glutamate and the activity of glutaminase to thrive just as much as the cancer cells, and our research has shown this metabolic pathway is essential for T cell anti-tumor activity,” the author said.
More than 1 in 3 lung adenocarcinomas have a common cancer-causing mutation in the gene KRAS – a powerful cancer driver. 

The research team had previously identified that the co-occurrence of additional mutations alters the properties of KRAS-mutant lung adenocarcinomas.

The senior author said the new findings built on this research, by showing how unique energy sources fuel the growth of tumors with different co-mutations, known as STK11/Lkb1 and KEAP1. The discovery was made possible by the sophisticated preclinical models used in the study. 

“Just like no two fingerprints are the same, we found the metabolite fingerprint of each co-occurring mutation altered the energy usage of KRAS-mutant lung adenocarcinoma,” the author said.

“This matters because the focus until now has predominantly been on key mutations, like KRAS

“Our work highlights the importance of investigating the other co-mutations without a ‘one-size-fits-all’ approach, because these additional mutations are critical in driving large changes in tumor biology that would impact treatment options and outcomes.”

Researchers say the glutaminase inhibitor could still have benefits for some patients when not combined with immunotherapy.

“We found tumors with the combination of KRAS and STK11/Lkb1 mutations produced elevated levels of glutamate that enable tumors to thrive in preclinical models,” the author said.

“So using the glutaminase inhibitor by itself would be beneficial for patients with this mutation profile. But combining immunotherapy with an inhibitor is unlikely to have positive outcomes.”

The team hopes their work will highlight the importance of considering model systems for examining complex questions on the tumor microenvironment, including metabolic profiles and immune cells. This is especially important when designing complex combination therapies.