Kathryn O'Donnell and her team at UT Southwestern Medical Center in Dallas have developed an experimental antibody called mAb7 that shrank tumors in preclinical models of non-small cell lung cancer, including those resistant to the current gold-standard treatment. The finding, published in Science Advances, opens a genuine therapeutic pathway for patients whose cancers have outsmarted existing drugs—a common and devastating problem in modern oncology.
Non-small cell lung cancer accounts for about 85% of all lung cancer cases in the United States and remains the leading cause of cancer-related deaths. The disease's grip tightens when it carries mutations in a gene called KRAS, found in roughly 25% of NSCLC cases. These mutations drive uncontrolled cell proliferation that fuels aggressive tumor growth. In 2024, the FDA approved adagrasib, a targeted drug that attacks KRAS-mutant NSCLC. Yet as with many breakthroughs in cancer treatment, patients inevitably develop resistance over time, leaving them with few meaningful options.
O'Donnell's lab had previously identified PCDH7, a protein on the surface of cancer cells, as a driver of NSCLC—especially in tumors with KRAS mutations. Building on that insight, the team collaborated with researchers at the University of Texas Health Science Center at Houston, Zhiqiang An, Ph.D., and Ningyan Zhang, Ph.D., to develop antibodies targeting PCDH7. From hundreds of candidates, they zeroed in on mAb7, an antibody that bound strongly to the protein, disrupted the cancer cells' internal signaling, and ultimately triggered cell death.
When researchers treated mice with KRAS-mutant NSCLC tumors with mAb7, the tumors shrank significantly. The results improved further when mAb7 was paired with trametinib, a drug that targets enzymes in the cancer-promoting RAS pathway. Most strikingly, this combination resensitized KRAS-mutant tumors to adagrasib, reducing tumor size substantially more than either drug alone achieved. The team also observed that PCDH7 was upregulated in tumors that had developed resistance to adagrasib—and critically, mAb7 effectively reduced the growth of those drug-resistant tumors.
To test whether the strategy might translate to humans, the researchers administered mAb7 in mice engineered to possess human immune systems. The results were encouraging: the antibodies recruited immune cells to attack the tumor cells, effectively eliminating them. "Overcoming resistance to molecularly targeted therapies is a critical unmet need for lung cancer patients," said O'Donnell. "We are excited that these antibodies may open another therapeutic avenue for lung cancer, especially for patients whose cancers have become resistant to KRAS inhibitors."
Nicole Novaresi, Ph.D., the study's first author and a postdoctoral researcher in O'Donnell's lab, emphasizes that mAb7 and related antibodies require substantial testing before reaching patients. But the path forward looks promising. These antibodies could eventually be used alone or in combination with adagrasib or other emerging therapies. Scientists are also exploring ways to enhance the antibodies—attaching chemotherapy drugs to them or engineering them to engage immune cells more powerfully. Beyond lung cancer, mAb7 may hold potential for treating pancreatic cancer, melanoma, and prostate cancer, all of which express PCDH7 on their surfaces.