New Insights into Aging and Lung Cancer Offer Hope for Targeted Therapies

Researchers at the University of Gothenburg have identified a protein, ATF4, linked to increased metastasis and recurrence in lung cancer, potentially paving the way for more effective, precision medicine approaches, particularly for older patients. The findings, published in Nature, address a long-standing paradox in lung cancer treatment and offer a new target for therapeutic intervention.

The Aging Paradox in Lung Cancer

Lung cancer disproportionately affects older individuals, yet traditional research often relies on younger animal models. This discrepancy has hindered the development of effective treatments for the elderly. Studies comparing lung tumors in young and old mice, alongside data from nearly one thousand lung cancer patients in Sweden’s Halland and Västra Götaland regions, revealed a striking pattern: older patients often present with smaller, slower-growing primary tumors that have already metastasized to other organs, such as the brain, liver, and bones.¹

How Aging Hijacks the Stress Response

The research highlights how aging alters the biology of lung cancer, making tumors more prone to spreading. The study identified a molecular signaling pathway where the stress-response protein ATF4 plays a crucial role. Normally, ATF4 is involved in the “integrated stress response,” protecting cells from stressors like nutrient deprivation or viral infections.¹ However, in older patients, tumors hijack this system.

“In older patients, this stress response is hijacked by the tumor, allowing cancer cells to reprogram their metabolism. The tumor does not grow faster, but this metabolic rewiring enables the cancer cells to spread and form metastases in other parts of the body,” explains Volkan Sayin, Associate Professor at the University of Gothenburg.¹

Tumors from older individuals, both in mice and humans, exhibited higher levels of ATF4. Elevated ATF4 levels were also associated with increased recurrence after lung surgery and poorer survival rates among patients with lung adenocarcinoma, the most common type of lung cancer.¹

Targeting ATF4 for New Therapies

The study suggests that blocking ATF4, or the metabolic processes it controls, could significantly reduce the spread of lung cancer in older individuals. In preclinical studies, researchers were able to dramatically reduce the spread of tumors in mice by targeting this pathway.²

“Our results indicate that these drugs may function significantly better if used more precisely, for example in older patients whose tumors show high ATF4 activity,” says Clotilde Wiel, Associate Professor at the University of Gothenburg.¹

The Need for Age-Appropriate Cancer Research

Current cancer treatments, like chemotherapy and radiation therapy, are primarily designed for rapidly growing tumors – a characteristic less common in older patients. The researchers emphasize the need for more research that considers the biological changes associated with aging.⁴

“It is very clear that normal aging fundamentally changes how tumors develop, a field of research where we currently lack a lot of knowledge,” Sayin concludes. “relatively little cancer research is conducted in age-appropriate models, as such studies are both very expensive and take a long time.”¹