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• Pharmacological inhibition of mutant KRAS has tumor-selective effects
• Novel agent MRTX1133 elicits potent disease control as a single agent
• Immune response shown to augment the therapeutic effect

News — BUFFALO, N.Y. — A research study led by a multidisciplinary team of scientists at Roswell Park Comprehensive Cancer Center details evidence on the therapeutic efficacy of a compound that targets a key genetic feature of pancreatic cancer. The work,  in Cancer Research, a journal of the American Association for Cancer Research, illustrates potential clinical applications for the novel anticancer agent MRTX1133 and outlines its effect on both the tumor and the surrounding environment. 

Most pancreatic cancers harbor mutations in the KRAS gene, which drives many of the features that make this disease so lethal. New precision agents have been developed that are selective for KRAS mutations. In this new work, the Roswell Park team explores the utility of a selective inhibitor, MRTX1133, that specifically targets KRASG12D — a mutation present in approximately half of all pancreatic cancers.

Mutation of KRAS is a major molecular driver for the development of pancreatic cancer. MRTX1133, being a selective inhibitor against mutant KRASG12D, possesses antitumor efficacy that is selective for only tumor cells that harbor this mutation — a level of precision targeting that has long been a goal for the treatment of cancer. The team used a series of laboratory cell lines and preclinical models to illustrate how the tumor itself, as well as the environment surrounding the tumor, is acted upon by MRTX1133 and how both contribute to the therapeutic response.   

“Our study highlights the importance of using models that accurately capture the tumor microenvironment,” says , the lead author on the new work. “This underscores the critical role of the tumor’s surrounding environment in therapeutic response to KRAS inhibition, which should be broadly considered when developing targeted therapies for pancreatic cancer.”

To date, immunotherapy has not been highly successful as treatment for pancreatic cancer. However, a key finding of the study was that MRTX1133 reprogrammed the immune system despite only inhibiting KRASG12D present in the tumor itself. In this fashion, the immune system contributed to potent therapeutic response in several of the pancreatic cancer models tested.

“Harnessing the immune system to act against the tumor is likely critical for the success of most cancer therapies. So it was especially exciting to see that pharmacological inhibition of KRAS had such profound effects on different elements of the immune system for which we are still exploring the mechanism,” notes study co-author , Associate Professor of Immunology at Roswell Park.

The lack of effective treatments for pancreatic cancer is a major contributor to poor survival rates, and new options are needed for those pancreatic cancer patients whose cancers are not controlled by standard therapies, the authors note. Currently the five-year survival rate for patients diagnosed with the disease in the U.S. is approximately 12%. 

“Agents that selectively target features unique to the tumor are critical for precision medicine, where scientific discovery ultimately provides new approaches to care,” says study senior author , Professor of Molecular and Cellular Biology and Director of the Advanced Tissue Imaging Shared Resource at Roswell Park. “Hopefully, such agents will become a much-needed game changer in the fight against pancreatic cancer.”

The research team also included , Chair of Molecular and Cellular Biology; , Assistant Professor of Molecular and Cellular Biology; and Costakis Frangou, PhD, Assistant Professor of Molecular and Cellular Biology.

This work was supported by the National Cancer Institute of the National Institutes of Health (grants CA267467, CA211878, R37CA275961, S10OD030410 and P30CA016056, Roswell Park’s Cancer Center Support Grant from the NCI) and by the Roswell Park Alliance Foundation. Drs. Witkiewicz and Knudsen are part of the Acquired Resistance to Therapy Network (ARTNET), a National Cancer Institute Moonshot project. All authors are members of the  at Roswell Park.

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From the world’s first chemotherapy research to the PSA prostate cancer biomarker, Roswell Park Comprehensive Cancer Center generates innovations that shape how cancer is detected, treated and prevented worldwide. Driven to eliminate cancer’s grip on humanity, the Roswell Park team of 4,000 makes compassionate, patient-centered cancer care and services accessible across New York State and beyond. Founded in 1898, Roswell Park was among the first three cancer centers nationwide to become a National Cancer Institute-designated comprehensive cancer center and is the only one to hold this designation in Upstate New York. To learn more about  and the , visit , call 1-800-ROSWELL (1-800-767-9355) or email [email protected].