Fox Chase Cancer Center Researchers Find Gene That Triggers Immune Response in Treatment-Resistant Small-Cell Lung Cancer

TREX1, a gene previously associated with autoimmune diseases, has been linked to small cell lung cancer. The discovery by Fox Chase Cancer Center scientists is a step toward understanding why this aggressive cancer is so resistant to treatment.

The findings are significant because they identify a pathway that could be targeted to make small cell lung cancer immunogenic, a quality that produces an immune response from the body. This could make the pathway sensitive to chemotherapy and immunotherapy.

“It’s very exciting, because if we can turn ‘cold’ tumors ‘hot,’ it could change the paradigm of small cell lung cancer in the clinic and open new venues to treat this difficult disease,” said Israel Cañadas, PhD, Assistant Professor in the Nuclear Dynamics and Cancer Research Program at Fox Chase. Cañadas is the corresponding author on the study, which was conducted with colleagues at Fox Chase and several other institutions.

Small cell lung cancer is a highly aggressive type of cancer with a five-year survival rate of less than 7%. While the disease initially responds well to chemotherapy, patients typically relapse, often within a matter of weeks. Tumors become “cold,” which means they aren’t recognized by the immune system.

“Once they relapse, these tumors are completely chemotherapy resistant,” Cañadas said. “They don’t respond to anything after that.”

Scientists have been searching for potential new targets to fight this disease. In the new study, the researchers began by scouring genetic data from small cell lung cancer cell lines for clues.

They noticed that the gene TREX1 was highly expressed in treatment-resistant tumor cells. This caught their attention, because TREX1 is known to be a regulator for an important immune pathway, where it blocks a mechanism involved in fighting viral infections.

“We thought this could be a mechanism for the cancer cell to survive the constant activation of the immune system during chemotherapy,” Cañadas said. Although the gene has previously been known to play a role in autoimmune diseases, it’s the first time it’s been associated with small cell lung cancer.

Researchers then used the genetic editing tool CRISPR to delete TREX1 from the cancer cells. Not only was the immune response activated again, but tumor growth slowed and the cancer cells became more sensitive to chemotherapy. They confirmed these results in both cell and mouse studies.

The team then conducted a genetic analysis of small cell lung cancer cells taken from 10 patients before and after treatment. They found that TREX1 expression increased in the cells after exposure to chemotherapy.

These findings are especially noteworthy since human samples of small cell lung cancer are rare. Because the disease spreads so quickly, most patients don’t have surgery to remove the tumors.

With TREX1 inhibitors already in development, the researchers hope to test these drugs against small cell lung cancer, first in cell and animal studies, and eventually in clinical trials with human patients.

The paper, “Targeting TREX1 Induces Innate Immune Response in Drug-Resistant Small-Cell Lung Cancer,” was published in Cancer Research Communications.