If clinicians could stop mutations of the KRAS gene in pancreatic cancer – which occurs in more than 90 percent of pancreatic cancer cases and significantly reduces the response to immunotherapy – the chances of treatment for this deadly type of cancer increases.
A collaborative study by scientists at Stony Brook University, published in Nature Communication, taking the first step toward a better understanding of how KRAS directs immune suppression and reveals a decrease in KRAS activity leading to a more favorable immune environment for fighting cancer.
Previous strategies to prevent oncogene KRAS therapeutically have been challenged by its growth-promoting role in cancer.
Instead, our study shows that oncogenic KRAS plays a major immune role in the maintenance of cancer, and that cancer treatment is improved by simultaneous inhibition of KRAS and its activation of the immune pathways that suppress the cancer. “
Oleksi Petrenko, PhD, Research Assistant Professor, Department of Microbiology and Ornithology, School of Rehabilitation Medicine, Stony Brook University
The researchers used a genetic laboratory model of pancreatic ductal adenocarcinoma (PDAC) to confirm that advanced tumor-level dependence on KRAS for tumor growth is reduced and manifested in antitumor immunosuppression. Cells lacking KRAS retain the ability to form tumors in immune mice. However, they do not suppress the immune system in wild-type immune mice, triggering a strong antitumor response.
“The main view of the paper’s conclusions is that mutations in KRAS not only stimulate tumor growth but also keep tumors ‘cold,’ rather than ‘hot’ when cytoxic T cells are ‘attacking the cancer cells,’ said co-author Scott Powers, Professor in the Department of Pathology at the School of Rehabilitation Medicine and Director of Clinical Cancer Genomics at Stony Brook University Cancer Center.
“We believe this study clearly demonstrates the potential of oncogenic KRAS to suppress the tumor immune responses,” says Nancy C. Reich, PhD, co-author and Professor in the Department of Microbio- knowledge and Immunology. ”It clarifies the need to develop therapeutic interventions that not only target KRAS pathways but also engage in immune cell defense. “
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Magazine Reference:
Ischenko, I., et al. (2021) KRAS drives immune dysfunction in a genetic model of pancreatic cancer. Nature Communication. doi.org/10.1038/s41467-021-21736-w.