New target to thwart multidrug resistance in cancer treatment
Study led by UTSW researchers reveals potential combination therapy to treat certain cancers
DALLAS – Feb. 25, 2025 – Multidrug resistance in cancer can be overcome by combining a drug that blocks a key enzyme with another anticancer drug, according to a study in preclinical models led by researchers at UT Southwestern Medical Center. The findings, published in Science Advances, could have implications for patients with certain cancers that have KRAS-G12C mutations after resistance to drug therapy develops.
“By overcoming resistance mechanisms, this combination therapy approach could improve treatment outcomes for patients with KRAS-G12C mutant cancers,” said the study’s lead author, Xinxin Song, M.D., Ph.D., Assistant Professor of Surgery at UT Southwestern and member of the Harold C. Simmons Comprehensive Cancer Center.
Cancers such as non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic ductal adenocarcinoma are driven by a mutant form of the KRAS protein that had long been considered undruggable. Such cancers have recently been treated with a KRAS-G12C inhibitor known as adagrasib, or MRTX849. However, emerging drug resistance to this therapy has presented challenges.
In order to investigate potential targets, Dr. Song, study leaders Daolin Tang, M.D., Ph.D., Professor of Surgery, and Rui Kang, M.D., Ph.D., Associate Professor of Surgery, and their colleagues first established the mechanism by which the mutant proteins were able to circumvent drug therapy. Using a variety of techniques, the researchers identified key steps in the complex cascade of cellular events that led to adagrasib becoming less effective. They found that one kinase, SRC, was key in this process.
Next, the researchers looked at more than 1,400 drug candidates and tested their ability to overcome the resistance that developed with adagrasib. They found that combining adagrasib with an SRC inhibitor called dasatinib improved the therapeutic efficacy against KRAS-G12C-mutated cells.
To test the potential clinical relevance of their findings, the researchers tested adagrasib both alone and together with dasatinib to determine their antitumor effects in both preclinical mouse models and human organoids. Bosutinib and DGY-06-116, a highly selective covalent SRC inhibitor, were also tested. Researchers found that by therapeutically targeting SRC, they could enhance or restore the anticancer activity of adagrasib.
“This research highlights the potential of targeting SRC kinase to prevent or overcome multidrug resistance after treatment with KRAS-G12C inhibitors,” Dr. Song explained. “Our findings could offer a transformative approach to improving therapeutic outcomes in certain KRAS-G12C mutant tumors.”
Other UTSW researchers who contributed to this research are John D. Minna, M.D., Director and Professor of the Hamon Center for Therapeutic Oncology Research, Professor of Internal Medicine and Pharmacology, and co-leader of the Experimental Therapeutics Research Program in the Simmons Cancer Center; Herbert J. Zeh, M.D., Chair and Professor of Surgery; Zhuan Zhou, Ph.D., Assistant Professor of Surgery; Boning Gao, Ph.D., Assistant Professor in the Hamon Center for Therapeutic Oncology Research and of Pharmacology; Chunhua Yu, M.D., Ph.D., Manager of the Tang Lab; and Ammar Elmezayen, Ph.D., postdoctoral researcher.
The SRC inhibitor DGY-06-116 was developed by Kenneth Westover, M.D., Ph.D. Chief of Lung Radiation Oncology Service, Director of Clinical Innovation and Information Systems for the Department of Radiation Oncology, and Associate Professor of Radiation Oncology and Biochemistry at UT Southwestern. Dr. Westover, who contributed to this study, is an inventor on a patent involving DGY-06-116.
Drs. Tang, Kang, Minna, Zeh, Zhou, Westover, and Gao are members of the Simmons Cancer Center.
This work was supported by grants from the National Institutes of Health (R01CA160417; R01CA229275; R01CA211070; CA070907; CA224065; CA142543; R01CA244341); The Welch Foundation (I-1829); Cancer Prevention and Research Institute of Texas (RP220145); American Cancer Society (IRG-21-142-16); Elsa U. Pardee Foundation (21005817); Anna Fuller Fund (21005962); and National Cancer Institute Cancer Center Support Grant (P30CA142543).
About UT Southwestern Medical Center
UT Southwestern, one of the nation’s premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty members have received six Nobel Prizes and include 25 members of the National Academy of Sciences, 23 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 3,200 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide care in more than 80 specialties to more than 120,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 5 million outpatient visits a year.