A fundamental discovery by University of Missouri scientists could help solve one of the most frustrating challenges in treating lung cancer: Why do some patients initially respond to drug treatment, only for it to stop working 18 months later?

The team, led by Dhananjay Suresh, Anandhi Upendran and Raghuraman Kannan at Mizzou’s School of Medicine, identified a hidden molecular “seesaw” involving two proteins inside cancer cells — AXL and FN14.

When investigators try to block one protein to stop the cancer, the other one takes over, helping the tumour survive.

Initially, scientists thought only blocking one protein — AXL — was the answer to stopping this problem.

So, in 2019, Suresh, then a graduate student at Mizzou, developed a treatment that focused on stopping it.

The only problem?

The tumour kept growing.

To fix this, Suresh, a research assistant professor of radiology at Mizzou, and colleagues have developed a new solution: a gelatin-based nanoparticle that can shut down both proteins at the same time.

So far, the results are promising: These nanoparticles deliver the treatment to the tumour site, and in early studies with mice, the tumours are responding to the dual-target treatment.

“If we can stop both sides of the seesaw from moving, we may finally be able to keep these drugs working,” Kannan, professor and the Michael J. and Sharon R.Bukstein Chair in Cancer Research, said.

“Our study shows that the tumour is successfully responding to the treatment, so these results will provide us with a solid foundation for further investigations.”

Working to stay one step ahead of cancer

According to the American Cancer Society, lung cancer is the leading cause of cancer-related death in the United States — claiming more lives each year than colon, breast and prostate cancers combined.

The lifetime risk of developing lung cancer is about one in 17 for men and one in 18 for women.

These sobering statistics underscore the significance of Kannan’s work, which focuses on advancing lung cancer research.

His research is particularly important for a subset of patients whose tumours carry a mutation in a certain gene that is present in approximately a quarter of cases.

While these patients initially respond well to tyrosine kinase inhibitors — targeted drugs precisely engineered to block the gene — tumours can eventually adapt.

“The tumour becomes smart, evolving mechanisms to resist treatment and continue growing despite continued drug therapy,” Kannan said.

While the Mizzou team’s dual-target therapy isn’t ready for hospitals yet, it marks a major step forward in understanding how drug resistance forms — and how to fight it.

Future research will explore whether this molecular seesaw effect happens in other types of proteins and continue testing this new approach, Upendran said.

“This helps fill in a huge black hole in our understanding of drug resistance,” Kannan, who also has an appointment in Mizzou’s College of Engineering, said.

“It gives us a new path forward — and fresh hope that lung cancer can become a manageable, chronic disease instead of a life-threatening one.”

“Nanoparticle-mediated cosilencing of drug resistance and compensatory genes enhances lung cancer therapy,” was published in the journal ACS Nano.

Soumavo Mukherjee, Ajit Zambre, Shreya Ghoshdastidar, Sairam Yadavilli, Karamkolly Rekha and Anandhi Upendran at Mizzou also contributed to the study.

Source: University of Missouri-Columbia