Immunotherapy may boost KRAS-targeted therapy in pancreatic cancer
A preclinical study from the Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center that combines RAS inhibition and immunotherapy shows promise for future clinical trials in pancreatic cancer treatment strategies.
1 min. read
Adding immunotherapy to a new type of inhibitor that targets multiple forms of the cancer-causing gene mutation KRAS has kept pancreatic cancer at bay in preclinical models for significantly longer than the same targeted therapy by itself, according to researchers from the Perelman School of Medicine and Penn Medicine’s Abramson Cancer Center. The results, published in Cancer Discovery, prime the combination strategy for future clinical trials.
Patients with pancreatic cancer have an overall poor prognosis: in most patients, the disease has already spread at the time of diagnosis, resulting in limited treatment options. Nearly 90% of pancreatic cancers are driven by KRAS mutations, the most common cancer-causing gene mutation across cancer types, which researchers long considered “undruggable.”
“We’ve been excited by the prospect of RAS inhibition for pancreatic cancer, which remains one of the deadliest and most difficult forms of cancer to treat,” says co-corresponding senior author Ben Stanger, the Hanna Wise Professor in Cancer Research and director of the Penn Pancreatic Cancer Research Center. “While the first wave of KRAS inhibitors have had limited impact in cancer care, this research shows that newer RAS inhibition tools may have an immune stimulatory effect, making them ideal to pair with immunotherapy for longer and better treatment response.”
In previous research, Stanger and co-corresponding author Robert Vonderheide, director of the Abramson Cancer Center, had shown that a small molecule inhibitor specifically targeting KRAS G12D, the form of the mutation more commonly found in pancreatic cancer, stimulated the immune system while shrinking tumors or stopping cancer growth in preclinical animal models of pancreatic cancer.
In this new study, the researchers used RAS(ON) multiselective inhibitors, the investigational agent daraxonrasib, and the preclinical tool compound RMC-7977. These inhibitors use a different mechanism of action than most other KRAS inhibitors to target the active or ON-state of multiple forms of RAS mutations.
The research team found that not only was RAS(ON) multiselective inhibition effective in preclinical pancreatic cancer models, but it was even more effective when combined with immunotherapy.
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