Jul 09, 2019 2:00 PM

One of the most significant obstacles cancer patients face is resistance to drug treatment. Aggressive tumors often become adept at resisting the powerful drugs used to combat them. Therapeutic agents that were effective at one point may become ineffective as a patient’s tumor evolves and learns to fight the drug.

A recent discovery by a team of scientists including Benjamin Myers, PhD, an investigator at Huntsman Cancer Institute (HCI) and assistant professor of oncological sciences at the University of Utah, could lead to a better understanding of how cancer patients develop drug resistance. The research also points to new strategies for designing drugs less likely to lead to resistance. The study was recently published in the journal Nature.

The research team, co-led by Myers and Aashish Manglik, MD, PhD, assistant professor of pharmaceutical chemistry at the University of California, San Francisco (UCSF), studied a protein called Smoothened that plays many vital roles in healthy tissue and organ development. However, when Smoothened becomes overactive, it can trigger the formation and spread of brain and skin tumors. Blocking Smoothened can stop cancer spreading, but eventually tumors adapt, making this approach ineffective.

The key to a potential solution for this problem came from a high-resolution molecular snapshot or X-ray structure of Smoothened, which gave the team an insight into how it becomes activated. They found that a molecule of cholesterol, commonly known for its role in atherosclerosis and cardiovascular disease, interacts directly with the portion of Smoothened that spans the cell membrane. “Sterols such as cholesterol are components of the cell membrane that affect many proteins such as Smoothened,” said Myers. The newly discovered interaction could represent an “Achilles’ heel” in Smoothened activation. Scientists will be able to capitalize on this finding to develop more effective treatments that tumors may not be able to circumvent.

Previous studies pointed at an important role for membrane sterols in Smoothened activation, but the importance of the X-ray structure is that it revealed the precise location within Smoothened where the cholesterol interacts. This information paved the way for follow-up studies showing that when Smoothened interacts with cholesterol at this site, it becomes activated. “The cholesterol molecule is in an ideal location: it induces a change in the shape of Smoothened, and this leads to activation. Our findings also help explain and reconcile puzzling observations from previous experiments regarding sterol effects on Smoothened activation,” Myers explained. The researchers’ next step is to apply their findings in the design of novel therapeutics that inhibit or prevent Smoothened activation.

Key collaborators on the project include Ishan Deshpande, PhD, a postdoctoral fellow in the Manglik Lab, and Danielle Hedeen, a doctoral student in the Myers Lab. Additional scientists involved in the study include Philip Beachy, PhD, Ron Dror, PhD, and members of their laboratories at Stanford University.

The work was supported by grants from the National Cancer Institute, including P30CA042014; the American Cancer Society; the Pew Charitable Trusts; the National Science Foundation; the Swiss National Science Foundation; and Huntsman Cancer Foundation.

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About Huntsman Cancer Institute at the University of Utah

Huntsman Cancer Institute at the University of Utah is the official cancer center of Utah and the only National Cancer Institute-designated Comprehensive Cancer Center in the Mountain West. The campus includes a state-of-the-art cancer specialty hospital and two buildings dedicated to cancer research. Huntsman Cancer Institute provides patient care, cancer screening, and education at community clinics and affiliate hospitals throughout the Mountain West. It is consistently recognized among the best cancer hospitals in the country by U.S. News and World Report. The region’s first proton therapy center opened in 2021 and a major hospital expansion is underway. Huntsman Cancer Institute is committed to creating a diverse and inclusive environment for staff, students, patients, and communities. Advancing cancer research discoveries and treatments to meet the needs of patients who live far away from a major medical center is a unique focus. More genes for inherited cancers have been discovered at Huntsman Cancer Institute than at any other cancer center, including genes responsible for breast, ovarian, colon, head and neck cancers, and melanoma. Huntsman Cancer Institute was founded by Jon M. and Karen Huntsman.

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