Researchers Identify Pathway That Drives Development of Cancer 'Stemness' and Drug Resistance
Most drugs used to treat lung, breast, and pancreatic cancers also promote drug resistance and ultimately spur tumor growth. Researchers at the University of California, San Diego, School of Medicine have discovered a biomarker called CD61 on the surface of drug-resistant tumors that may be responsible for inducing tumor metastasis by enhancing the stem cell–like properties of cancer cells. The findings, published online in Nature Cell Biology, may point to new therapeutic opportunities for reversing drug resistance in a range of cancers, including those in the lung, pancreas, and breast.
“There are a number of drugs that patients respond to during their initial cancer treatment, but relapse occurs when cancer cells become drug-resistant,” said David Cheresh, PhD, Distinguished Professor of Pathology and UC San Diego Moores Cancer Center Associate Director for Innovation and Industry Alliances. “We looked at the cells before and after they became resistant and asked, ‘What has changed in the cells?’”
Cancer Stem Cells Linked to Drug Resistance
Dr. Cheresh and colleagues investigated how tumor cells become resistant to drugs like the tyrosine kinase inhibitors erlotinib (Tarceva) or lapatinib (Tykerb). They found that as drug resistance occurs, tumor cells acquire stem cell–like properties that give them the capacity to survive throughout the body and essentially ignore the drugs.
Specifically, the scientists delineated the molecular pathway that facilitates both cancer “stemness” and drug resistance, and were able to identify existing drugs that exploit this pathway. These drugs not only reverse stem cell–like properties of tumors, but also appear to resensitize tumors to drugs to which the cancer cells had developed resistance.
“The good news is that we’ve uncovered a previously undefined pathway that the tumor cells use to transform into cancer stem cells and that enable tumors to become resistant to commonly used cancer drugs,” said Dr. Cheresh.
Upcoming Study
Based on these findings, Hatim Husain, MD, Assistant Professor at Moores Cancer Center, has designed a clinical trial targeting this pathway in patients whose tumors are drug-resistant. The trial will be open to patients with lung cancer who have experienced cancer progression and resistance to erlotinib. It is expected to begin in the next year.
“Resistance builds to targeted therapies against cancer, and we have furthered our understanding of the mechanisms by which that happens,” said Dr. Husain. “Based on these research findings we now better understand how to exploit the ‘Achilles heel’ of these drug-resistant tumors. Treatments will evolve into combinational therapies where one may keep the disease under control and delay resistance mechanisms from occurring for extended periods of time.”
Although the trial is expected to begin with patients who have already experienced drug resistance, Dr. Husain hopes to extend the study to reach patients in earlier disease stages to prevent initial resistance.
Dr. Cheresh is the corresponding author for the Nature Cell Biology article.
This research was funded, in part, by the National Institutes of Health, the National Cancer Institute, the Association pour la Recherche contre le Cancer, and La Fondation Philippe.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
