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Stopping Mutant KRAS Could Lead to Enhanced Therapies for Pancreatic Cancer

Images showing KRAS intact in tumor tissue and knocked out in a laboratory model of PDAC.

STONY BROOK, NY, March 10, 2021 — If clinicians could stop mutations of the KRAS gene in pancreatic cancer – which happens in more than 90 percent of pancreatic cancer cases and drastically reduces response to immunotherapy – the chances of improving treatment for this deadly form of cancer would be increased. A collaborative study by Stony Brook University scientists, published in Nature Communications, takes an initial step toward better understanding how KRAS drives immune evasion and demonstrates a lowering of the KRAS activity resulting in a more favorable immune environment to fight cancer.

Previous strategies to block the KRAS oncogene therapeutically have focused on counteracting its growth-promoting role in cancer.

“Instead, our study shows that oncogenic KRAS plays a profound immunosuppressive role in cancer maintenance, and that treatment of cancer will be improved by simultaneously inhibiting KRAS and activating immune pathways suppressed by the cancer,” says Oleksi Petrenko, PhD, Research Assistant Professor in the Department of Microbiology and Immunology in the Renaissance School of Medicine at Stony Brook University.

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Images showing KRAS intact in tumor tissue and knocked out in a laboratory model of PDAC.

The researchers used a genetic a laboratory model of pancreatic ductal adenocarcinoma (PDAC) to demonstrate that at an advanced tumor stage dependence on KRAS for tumor growth is reduced and is manifested in the suppression of antitumor immunity. KRAS-deficient cells retain the ability to form tumors in immunodeficient mice. However, they fail to evade the immune system in immunocompetent wild-type mice, triggering a strong antitumor response.

“The key insight of the paper’s findings is that mutations in KRAS not only promote tumor growth but also keep tumors ‘cold,’ rather than ‘hot’ when cytoxic T-cells are attacking the cancerous cells,” says co-author Scott Powers, Professor in the Department of Pathology in the Renaissance School of Medicine and Director of Clinical Cancer Genomics at the Stony Brook University Cancer Center.

“We believe that this study clearly demonstrates the ability of oncogenic KRAS to corrupt our anti-tumor immune responses,” adds Nancy C. Reich, PhD, co-author and Professor in the Department of Microbiology and Immunology. “It highlights the need to develop therapeutic interventions that not only target KRAS pathways but that engage immune cell defense.”

The research was supported in part by the National Institutes of Health’s National Cancer Institute (NCI — grants R01CA217206, R01AI105114, and R01CA236389 – the Carol M. Baldwin Breast Cancer Research Award (to Reich), and the Catacosinos Cancer Research Award (to Petrenko).

About Renaissance School of Medicine at Stony Brook University:

Established in 1971, Renaissance School of Medicine at Stony Brook University includes 25 academic departments. The three missions of the School are to advance the understanding of the origins of human health and disease; train the next generation of committed, curious and highly capable physicians; and deliver world-class compassionate healthcare. As a member of the Association of American Medical Colleges (AAMC) and a Liaison Committee on Medical Education (LCME) accredited medical school, Stony Brook is one of the foremost institutes of higher medical education in the country. Each year the School trains nearly 500 medical students and more than 600 medical residents and fellows. Faculty research includes National Institutes of Health-sponsored programs in neurological diseases, cancer, cardiovascular disorders, biomedical imaging, regenerative medicine, infectious diseases, and many other topics. Physicians on the School of Medicine faculty deliver world-class medical care through more than 31,000 inpatient, 108,000 emergency room, and 940,000 outpatient visits annually at Stony Brook University Hospital and affiliated clinical programs, making its clinical services one of the largest and highest quality medical schools on Long Island, New York. To learn more, visit www.medicine.stonybrookmedicine.edu.

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