By Christopher Vaughan

October 19, 2020

Non-small-cell lung cancer is deadly—it is one of the most common cancers, and though treatments like radiation, chemotherapy, and immunotherapy work in some patients, many of these tumors are resistant to treatment.  Together, these factors make non-small-cell lung cancer the number one cause of all cancer deaths worldwide. 

Institute researcher Maximilian Diehn, MD, PhD, and his colleagues have spent years understanding why this deadly cancer is treatment resistant and trying to find ways around the cancer’s defenses. The researchers have now done an extensive survey of lung cancer mutations to find which ones induce resistance to radiation and discovered that mutations in two genes appear to be responsible for a large fraction of recurrences of the cancer after treatment.

“The way that radiation kills cancer is by creating free-radical molecules inside the cancer cells,” Diehn said. “These highly reactive molecules damage the DNA of a cell and cause it to die.” 

Because free radicals are so dangerous, cells have specific defenses against them. Unfortunately, some lung cancer cells are even better than normal cells at defending themselves against free radicals, and Dr. Diehn’s team has identified a type of non-small-cell lung cancer that is a black belt in free radical self-defense. 

Diehn and his colleagues had found in previous research that mutations in two particular genes that control free radical defenses, KEAP1 and NRF2 (also known as NFE2L2), make the tumors much better at resisting radiation treatment. “In the new study, we validated our findings that patients with mutations in these genes were much more likely to have a recurrence of their cancer after radiation treatment, indicating that radiation was unable to kill all the cancer cells,” Diehn said. 

The scientists also looked at some patients who had undergone treatment with stereotactic radiation—a very focused, high-dose radiation that can be used in early-stage lung cancer. “Surprisingly, we found that patients with these mutations, even when given a higher dose of radiation, still had a high recurrence risk of cancer after treatment, indicating that higher doses of radiation are not the answer in most cases.”

As a control, the researchers looked at patients with and without the gene mutations who had undergone surgery instead of radiation. “We found that there was no difference in recurrence rates between the two groups who had undergone surgery,” Diehn said. “This indicates that tumors with these mutations are specifically resistant to radiation but not surgery.” 

The researchers also looked for mutations in other genes that would provide the same predictive power of cancer recurrence after radiation. “We could not find any, suggesting that mutations in KEAP1 and NFE2L2 are the dominant biological drivers of radiation resistance in non-small cell lung cancer.” In fact, Diehn says, almost half of all cancer recurrence occured in patients with mutations in these genes. 

Taking their work into the laboratory, the team found that not all mutations are created equal. The researchers placed mutations from individual patients into cell lines—each patient has a slightly different mutation in these genes—and found which mutations conferred radiation resistance and which ones didn’t. The cell line results agreed with the patient data, confirming the biological link between the mutations and resistance.

Finally, they wondered if it could be possible to sensitize tumor cells with KEAP1 or NFE2L2 mutations to radiation. After trying several strategies, they found that a drug targeting glutaminase (a protein involved in production of free radical defenses) and which is already in clinical trials in other contexts can preferentially sensitize mutant cells to radiation. “Based on our data, glutaminase inhibition appears to be an extremely promising approach for overcoming the radioresistance caused by these mutations, and we are eager to test this strategy in the clinic,” Diehn said.

Overall, the research has significant clinical implications. For example, patients whose tumors have KEAP1 or NFE2L2 mutations and who are candidates for both radiation and surgery might have better outcomes with surgery, Diehn says. In the future, it is possible that adding drugs such as glutaminase inhibitors to radiation could lead to better outcomes for patients with these mutations. The team is already planning clinical studies exploring treatment personalization based on their findings with the hopes of improving the number of patients with lung cancer who can be cured.

Diehn is a member of the Stanford Institute for Stem Cell Biology and Regenerative Medicine, the Stanford Cancer Institute, and the Department of Radiation Oncology.