Moffitt Study Shows How Tumor Support Cells Help Lung Cancer Evade Targeted Therapy

Moffitt Study Shows How Tumor Support Cells Help Lung Cancer Evade Targeted Therapy

Key Highlights

• Tumor support cells called fibroblasts can help lung cancer cells survive targeted treatments, even when those drugs successfully block cancer-driving genes.

• Fibroblasts protect cancer cells through two distinct mechanisms. First, by releasing growth-promoting proteins and then by physically supporting tumors through adhesion-based signals.

• Blocking just one survival pathway is not enough. Researchers found that targeting multiple pathways at the same time is necessary to overcome drug resistance.

• Advanced proteomics technology allowed researchers to untangle complex cell-to-cell signaling, revealing which survival signals came from cancer cells versus surrounding fibroblasts.

• Findings could help guide more personalized combination therapies for patients with ALK-driven lung cancer and potentially other tumor types in the future.

TAMPA, Fla. (Jan. 7, 2026) - A study led by researchers at Moffitt Cancer Center found that normal cells surrounding a tumor, known as cancer-associated fibroblasts, can help lung cancer cells survive targeted drug therapy by activating multiple survival routes that allow tumors to evade treatment. Results of the study, published in Science Signaling, provide valuable insights into why some cancers are resistant to currently approved therapies.

The findings explain how fibroblasts send dual help signals to cancer cells. First through soluble protein factors released into the environment, and second through physical interactions that trigger separate survival pathways. The study found that blocking just one of these pathways is not enough. A combined approach is required to fully remove fibroblast-mediated protection.

This understanding could guide the future design of personalized combination therapies that more effectively overcome drug resistance in patients with ALK-driven lung cancer and potentially other tumor types.

Q&A with Uwe Rix, Ph.D., lead author and senior member in the Molecular Medicine Program at Moffitt.

Why did researchers look at fibroblasts when studying treatment resistance?

Fibroblasts don't just sit next to cancer cells, they interact with them in ways that can change how the cancer responds to treatment. Previous work showed they can activate pathways that protect cancer cells. Because most studies looked at single mechanisms, we wanted to dig deeper into all the ways fibroblasts support cancer, so that better therapies could be designed to block those protective effects.

How do fibroblasts help cancer cells survive targeted treatment?

Fibroblasts help in two main ways. First, they release proteins that act like "chemical signals," turning on growth and survival pathways in the cancer cells that the drug is supposed to shut off. One of these proteins is called HGF, which turns on the MET pathway. Second, when fibroblasts physically touch cancer cells, they create a structural support network using proteins like fibronectin that trigger a different survival signal through integrins. Both types of signals help tumors resist treatment, so both need to be blocked to eliminate the support.

What new technology did your team use to study these interactions?

We used a clever tagging method to tell apart signals from the cancer cells versus the fibroblasts even when the two were mixed together. Next, we engineered each cell type to use slightly different molecular building blocks and then detected those differences using mass spectrometry. This allowed us to see exactly which signals came from the cancer cells and which came from the fibroblasts, an important distinction for developing therapies that target cancer cells while sparing normal cells.

Why isn't blocking just one survival pathway enough to stop cancer cells?

Cancer cells come from normal cells and share many of the same pathways that help normal cells survive and grow. Because cancer cells lose the normal controls that tell them when to stop, they become dependent on certain signals. If one pathway is blocked, the cancer cell can find another way around the roadblock. By targeting both the main driver of cancer growth and the backup survival pathway at the same time, therapies stand a better chance of killing the cancer cells.

How might these findings help doctors choose better treatments for patients?

Rather than focusing only on the genetic features of a tumor, it may also be helpful to look at what proteins fibroblasts around the tumor are making. If we know which fibroblast signals are present, we may be able to predict which combinations of drugs will be most effective for a specific patient's tumor.

What are the next steps before this research can impact patient care?

This study shows how complex tumors can be and why single-drug treatments often fail. Some cancers may require multi-pathway targeting, which raises concerns about side effects. However, many approved drugs already hit more than one target, and with better understanding and smart combinations, it may be possible to design treatments that are both effective and tolerable. We are also exploring treatment schedules that use additional drugs only at critical times to maximize benefit while minimizing side effects.

This study was supported by the National Cancer Institute (R01-CA219347, P30-CA076292) and the Florida Department of Health Bankhead-Coley Cancer Research Program (30-20450-9901).

About Moffitt Cancer Center
Moffitt is dedicated to one lifesaving mission: to contribute to the prevention and cure of cancer. The Tampa-based facility is one of only 58 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt's scientific excellence, multidisciplinary research, and robust training and education. Moffitt's expert nursing staff is recognized by the American Nurses Credentialing Center with Magnet® status, its highest distinction. For more information, call 1-888-MOFFITT (1-888-663-3488), visit MOFFITT.org, and follow the momentum on Facebook, X, Instagram and YouTube.

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