Pancreatic cancer, malignant tumor of pancreas with KRAS mutation
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Researchers at the University of Pennsylvania School of Medicine, have shown that a small molecule inhibitor of the cancer-causing gene mutation KRAS successfully shrinks tumors and stops cancer growth in preclinical models for pancreatic cancer.

Found in nearly 30 percent of all human tumors, KRAS is one of the most common gene mutations linked to cancer. KRAS is especially prevalent in pancreatic cancer with nearly 90 percent of pancreatic cancers driven by a mutation in the gene. Unfortunately, despite being widespread the mutation remains difficult to target.

Reporting in Cancer Discovery scientists at the University of Pennsylvania School of Medicine used a small molecule inhibitor of KRAS, called MRTX1133 to specifically target a KRAS mutation causing pancreatic cancer. The researchers were able to show that the KRAS-inhibitor not only directly targets cancer cells but also cooperates with the immune system to produce a durable response to treatment reducing the chances of cancer cells finding ways to evade targeted therapy.

“The results of this study are in stark contrast to anything we’ve seen before in pancreatic cancer,” said Ben Stanger, PhD, professor in cancer medicine at the University of Pennsylvania School of Medicine and senior author of the study. “Even in preclinical research models for this cancer type, most drugs tested within the last decade—including novel immunotherapies—have had limited impact.”

The preclinical model used in the study allowed the researchers to assess the impact of the small molecule inhibitor on the immune system by letting the tumor evolve after implantation in otherwise healthy mice. Using this technique, the scientists were able to analyze the small molecule KRAS-inhibitors impact on the tumor microenvironment.

According to the researchers, the drug led to an increase of T cells in the tumor microenvironment improving the depth and duration of the response to MRTX1133. In models without T cells, the effect of the KRAS-inhibitor was decreased and the tumors more likely to return, suggesting that the drug could be combined with immunotherapy to improve the long-term response in pancreatic cancer.

“After many years of work to find much-needed new approaches for patients with pancreatic cancer, it’s exciting to have a new class of drugs on the horizon,” said co-author and professor at the University of Pennsylvania Abrams Cancer Center Robert Vonderheide, PhD, in a press statement. “We’re optimistic that KRAS G12D inhibitors will make their way into clinical trials soon. KRAS is surrendering, and now we know the immune system can see it.”

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