Novel enzyme that fuels lung tumor growth could be ‘perfect’ drug target

By Samar Mahmoud, MS, for MDLinx
Published December 11, 2018

Key Takeaways

Suppression of a newly discovered enzyme reduced tumor growth in mouse models, suggesting it could be used as a therapeutic target for lung cancer and other cancer types, according to a recent study in Cell Reports.

Researchers at the University of Texas Southwestern Medical Center (UT Southwestern), Dallas, TX, identified an enzyme—transmembrane serine protease 11B (TMPRSS11B)—that is highly expressed in lung squamous cell carcinoma. TMPRSS11B was also found in prostate cancer as well as in squamous cell head, neck, and cervical cancers.

In prior studies, investigators had shown that upregulation of TMPRSS11B mRNA was correlated with poor prognosis in patients with non-small cell lung cancer. This information suggested TMPRSS11B plays a key role in promoting tumorigenesis, prompting researchers to investigate this enzyme further.

“In this study, we found that the enzyme strongly promoted the growth of certain types of lung cancer cells. We uncovered a new mechanism that expands our understanding of how cancer cells reprogram their metabolism to provide energy for rapid growth as they form tumors,” said principal investigator Kathryn O’Donnell, PhD, assistant professor, Department of Molecular Biology, UT Southwestern.

New therapeutic strategy?

To validate these findings, the researchers inhibited the enzyme’s function by using shRNA-mediated knockdown and CRISPR-mediated genome editing. They found that inhibiting TMPRSS11B strongly repressed tumorigenesis, suggesting that targeting this enzyme could provide a novel therapeutic strategy for the treatment of lung squamous cell carcinoma.

The researchers discovered that TMPRSS11B interacts with two proteins, MCT4 and Basigin, at the plasma membrane. This interaction is critical for lactate export, which promotes tumorigenesis. In previous work, the researchers had shown that lactate—once thought to be a waste product—is an important fuel source for growing cancer cells.

“Tumors make and consume large quantities of lactate,” said the study’s lead author Barrett L. Updegraff, a graduate student in Dr. O’Donnell’s laboratory. “Transport of this nutrient impacts disease progression in lung cancer. We found that some lung tumors enlist the help of TMPRSS11B to assist in lactate transport to facilitate tumor growth.”

Dr. O’Donnell added: “In addition to providing fuel, it is thought that lactate can suppress the immune system. Investigating whether this enzyme can influence the immune system’s ability to attack tumors will be an important direction for future research.”

The perfect cancer drug target

According to Dr. O’Donnell, TMPRSS11B is found on the surface of cancer cells, which makes it a potential target for antibody-based therapeutic strategies. Furthermore, the enzyme appears to be absent in healthy cells, which is promising because targeting TMPRSS11B could produce a treatment that is less toxic than current chemotherapeutic agents.

Future work in Dr. O’Donnell’s laboratory will focus on detailed, mechanistic studies to determine exactly how TMPRSS11B promotes lactate export. Researchers anticipate using this information to begin investigating potential therapeutic strategies to target this enzyme.

“In TMPRSS11B, we have the perfect cancer drug target—it’s accessible on the tumor cell surface, it's selective for cancer cells, blocking it both inhibits the cancer growth and sets the stage for developing better immunity against the cancer, and its presence makes it a diagnostic for which patients to treat,” said study co-author John Minna, MD, professor, Departments of Pharmacology and Internal Medicine, and director, Hamon Center for Therapeutic Oncology Research, UT Southwestern.

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