HMN 2026: How New antibody may boost KRAS-targeted lung cancer treatment after resistance emerges

An experimental antibody treatment that binds to a protein known as PCDH7 shrank tumors in preclinical models of non-small cell lung cancer (NSCLC), including those resistant to a targeted therapy, a study led by UT Southwestern Medical Center researchers showed. The findings, published in Science Advances, could eventually lead to a new class of drugs to treat NSCLC and potentially other cancers.

“Overcoming resistance to molecularly targeted therapies is a critical unmet need for lung cancer patients. 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,” said Kathryn O’Donnell, Ph.D., associate professor of molecular biology and a member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. O’Donnell co-led the study with first author Nicole Novaresi, Ph.D., a postdoctoral researcher in the O’Donnell Lab, and collaborators at the University of Texas Health Science Center at Houston.

NSCLC accounts for about 85% of lung cancer cases in the U.S. and is the leading cause of cancer-related deaths. The O’Donnell Lab focuses on identifying and characterizing proteins on the surface of NSCLC and other cancer cells because of their potential as therapeutic targets. In 2017, O’Donnell and her colleagues identified PCDH7 as a driver of NSCLC, especially in tumors with mutations in a gene called KRAS. Found in about 25% of NSCLC cases, these mutations cause uncontrolled cell proliferation that propels tumor growth.

In 2024, the Food and Drug Administration approved a drug called adagrasib, which targets NSCLC with KRAS mutations. However, patients inevitably develop resistance to this treatment over time, leaving them with few therapeutic options.

Searching for a new way to attack NSCLC, O’Donnell’s group collaborated with Zhiqiang An, Ph.D., and Ningyan Zhang, Ph.D., at the University of Texas Health Science Center to develop antibodies that target PCDH7. The teams then worked closely to characterize and functionally evaluate them. Starting with hundreds of antibody candidates, the researchers narrowed their focus to an antibody called mAb7 that bound strongly to PCDH7, reduced intracellular signaling and proliferation in NSCLC cells, and eventually caused the cancer cells to die.

When the scientists treated mice with KRAS-mutant NSCLC tumors with mAb7, the tumors shrank significantly. This effect was enhanced when mAb7 was delivered with a drug called trametinib, which targets MAPK/ERK enzymes in the cancer-promoting RAS pathway. This treatment also sensitized the KRAS-mutant NSCLC tumors to adagrasib, reducing tumor size significantly more than mAb7 or adagrasib alone. The team also found that PCDH7 was upregulated in tumors that eventually developed resistance to adagrasib and that mAb7 reduced the growth of those drug-resistant tumors.

To get a sense of whether this strategy might work in patients, the researchers tested mAb7 in mice engineered to have human immune systems. A closer look showed that the antibodies brought immune cells to the human tumor cells and effectively eliminated the cancer cells.

These novel antibodies will require significant testing before use in patients, Novaresi said. But eventually, they may be used alone or in combination with adagrasib or other emerging targeted cancer therapies. Enhancing them by attaching chemotherapy drugs or by engaging immune cells could help the antibodies fight NSCLC even more effectively. She added that mAb7 may also have the potential for treating additional cancers that produce PCDH7 on their cell surfaces, including pancreatic cancer, melanoma and prostate cancer.

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