Fibroblasts Help Lung Tumors Outsmart Targeted Therapy

The study focused on a specific subset of lung cancer known as ALK-rearranged lung adenocarcinomas—a form of non-small cell lung cancer (NSCLC) driven by genetic alterations in the ALK gene, affecting approximately 6% of patients. These tumors typically respond well to ALK inhibitors, a class of targeted drugs, but resistance inevitably develops.

Using sophisticated 3D “spheroid co-culture” models that simulate the tumor microenvironment, researchers co-cultured ALK-rearranged tumor cells with cancer-associated fibroblasts (CAFs)—cells that surround and support tumors. This setup enabled them to observe cell-to-cell interactions and treatment responses more accurately than traditional cell cultures. In a series of experiments, the researchers looked at how CAF- secreted substances influenced the cancer cells’ ability to survive, grow, and process lipids, as well as how they impacted signals inside the cells that help them function. The scientists also tested whether they could slow down or kill the cancer cells by blocking their lipid-processing abilities or by triggering a special type of cell death called ferroptosis (a form of cell death driven by lipid peroxidation).

“We discovered that fibroblasts in the tumor microenvironment can reactivate survival pathways and rewire lipid metabolism in lung cancer cells, making them resistant to ALK inhibitors,” explains Dr. Ann-Kathrin Daum, first author of the study. The researchers found that CAFs secrete factors such as HGF and NRG1, which stimulate lipid biosynthesis and activate the AKT signaling pathway in cancer cells. These metabolic changes not only suppress cell death but also promote proliferation—blunting the effects of ALK-targeted drugs. Notably, combining ALK inhibitors with drugs that block lipid metabolism or induce ferroptosis restored drug sensitivity in resistant tumor models.

"This insight opens up new opportunities to combine targeted therapies with drugs that block this metabolic support and help overcome non-genetic resistance mechanisms,” added Prof. Petros Christopoulos, senior co-author and a leading expert in ALK-rearranged lung cancer. The study highlights the importance of understanding the cell-to-cell interaction in the tumor microenvironment and could contribute to improved clinical strategies by combining ALK inhibitors with metabolic therapies.

The DZL-funded study was published in the journal Cancer & Metabolism.

Source: Fibroblasts Help Lung Tumors Outsmart Targeted Therapy - TLRC Heidelberg

Original Publication: Daum AK, Schlicker L, Schneider MA, Muley T, Klingmüller U, Schulze A, Thomas M, Christopoulos P, Sültmann H. Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis. Cancer Metab. 2025 Jun 16;13(1):28. doi: 10.1186/s40170-025-00400-7.