Through a highly collaborative research effort led by the laboratory of Saïd Sebti, Ph.D, at the VCU Massey Comprehensive Cancer Center, a team of scientists has successfully developed a groundbreaking targeted therapy that hones in on the KRAS protein that drives some of the deadliest human cancers, including pancreatic, lung and colon tumors.
Their findings — published in Cancer Research Communications — suggest that a novel inhibitor drug could be used to target KRAS G12D, a subset of the notorious cancer-driving KRAS gene.
This research involved the combined efforts of scientists from multiple cancer centers, including three National Cancer Institute-designated cancer centers (Moffitt Cancer Center, Montefiore Einstein Comprehensive Cancer Center, University of Florida Health Cancer Center) and the Cancer Center at Illinois.
For this particular study, Sebti’s team screened a library of compounds in partnership with the Cancer Center at Illinois to identify drugs that attach themselves to KRAS and thwart it, preventing it from causing cancer.
The most potent drug they identified through this process, KRAS Binder-456 (KRB-456), was then evaluated by Sebti and his team to understand its biological mechanism of action.
They demonstrated that KRB-456 significantly inhibits the growth in mice of mutant KRAS-addicted tumors derived from pancreatic cancer patients who had not responded to, or relapsed following, traditional chemotherapy or radiation therapy.
Sebti said further investigation is planned to test this drug in combination with standard-of-care therapeutic options to explore its potential as an effective supplement to cancer treatment, or to possibly inform the development of a more potent or selective drug against KRAS G12D-driven tumors.
More than 90% of pancreatic cancers, about 35% of colon tumors and roughly one-quarter of lung tumors have a mutant KRAS gene, Sebti said.
Through innovative collaborations and cutting-edge technology, the lab strives to unravel the complexities of cancer and develop novel strategies for effective treatment of disease.
Aslamuzzaman Kazi, Alok Ranjan, Vasantha Kumar M.V., Bogos Agianian, Martin Garcia Chavez, Vignesh Vudatha, Rui Wang, Rajanikanth Vangipurapu, Liwei Chen, Perry Kennedy, Karthikeyan Subramanian, Jonathan C.K. Quirke, Francisca Beato, Patrick Underwood, Jason B. Fleming, Jose Trevino, Paul J. Hergenrother, Evripidis Gavathiotis, Said M. Sebti. Discovery of KRB-456, a KRAS G12D switch-I/II allosteric pocket binder that inhibits the growth of pancreatic cancer patient-derived tumors. Cancer Research Communications, 2023; DOI: 10.1158/2767-9764.CRC-23-0222
Virginia Commonwealth University. (2023, December 18). Promising anticancer drug targeting KRAS protein. ScienceDaily. Retrieved December 26, 2023 from www.sciencedaily.com/releases/2023/12/231218125931.htm
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