With recent data that RAS inhibition can improve survival in metastatic pancreatic cancer,1 the optimization of these agents has become a research priority. Minh Than, MD, PhD, a clinical and research fellow in Hematology-Oncology at Penn Medicine and colleagues have proposed an unorthodox approach: giving these drugs before cancer develops—a concept called “interception.”
In a preclinical study in mice, Dr. Than reported at the 2026 AACR Annual Meeting, the RAS(ON) multiselective inhibitor RMC-7977 eliminated KRAS-mutant precancerous cells in the pancreas—pancreatic intraepithelial neoplasia (PanIN)—before they could become malignant.2
Genetically engineered KPC mice (KRASG12D/+; Trp53R172H/+; P48-Cre) treated prophylactically with RMC-7977 nearly doubled their overall survival, as compared to treatment after tumors developed, Dr. Than reported in a late-breaker abstract presented at the meeting.
“KRAS-directed cancer interception delays tumor onset and profoundly extends survival of high-risk KPC animals. RAS(ON)-targeted therapy before tumor formation led to a superior survival benefit compared to treatment after tumor formation,” he said.
“KRAS inhibition can eliminate PanIN. If you eliminate PanIN, you can delay tumor onset and prolong overall survival. If you ‘intercept,’ it may be easier to impede on pre-cancer, rather than trying to catch up to it later,” he added.
Dr. Than theorized why this approach could be more effective. “We know that RAS inhibition alone will be insufficient to cure this disease, because tumor heterogeneity and cellular plasticity are persistent issues when we deal with single-agent interventions…Cancer is a Darwinian process, and with all this variation it’s no surprise that there will be a cell that survives a therapeutic insult,” he said. “We present to you an idea—cancer interception—where we intervene on precancerous cells to impair their ability to become cancer. Ultimately, this can avoid all the heterogeneity and the plasticity that may be seen in later stages of the disease.”
PanIN is frequent in healthy pancreata, although most of these lesions do not progress to cancer. Interception could target individuals with known risk factors for pancreas cancer, he said.
Study Details
Using the gold-standard KPC mouse model, the investigators first established that PanIN disappears in response to RAS inhibition, utilizing either multi-selective or mutant-selective inhibitors.They then determined that exposure to RAS inhibition was associated with cell death in PanIN cells, explaining how these lesions were disappearing.
The next question was whether eliminating PanIN was altering the natural history of pancreatic cancer. Indeed, as observed with highly sensitive high-resolution ultrasound, 4 weeks of RAS inhibition alone significantly delayed the onset of tumor development. That delay translated into an overall survival benefit, with a median overall survival of 199 days after interception as compared to 120 days for control mice (P < .0001), he reported.
The use of metronomic dosing—RAS inhibition every other week—resulted in even more prolonged survival. Median overall progression-free survival was 329 days in intercepted mice vs 105 days in control mice (P < .0001), and median overall survival was 376 days vs 138 days (P < .0001), respectively.
The key question was whether interception was superior to treatment after tumor development, which had prolonged survival by about 2 months. They found that median overall survival was 138 days for control (untreated) mice with PanIN, 200 days for mice treated for their tumors, and 376 days for the “intercepted” mice, so the preemptive approach nearly doubled survival over conventional treatment.
“The oldest mouse under KRAS-directed interception lived about 600 days, which is close to the lifespan of a KRAS wild-type mouse. I think this is a testament to the power and potential of cancer interception over treatment,” Dr. Than commented.
Dr. Than conducted the research along with Ben Stanger, MD, PhD, Director of the Penn Pancreatic Cancer Research Center, and Robert Vonderheide, MD, DPhil, FAACR, Director of the Abramson Cancer Center. ν
DISCLOSURE: Dr. Than had no relevant disclosures.
REFERENCES
1. Revolution Medicines: Daraxonrasib demonstrates unprecedented overall survival benefit in pivotal phase 3 RASolute 302 clinical trial in patients with metastatic pancreatic cancer. https://ir.revmed.com/news-releases/news-release-details/daraxonrasib-demonstrates-unprecedented-overall-survival-benefit. Accessed April 22, 2026.
2. Than MT, Dequiedt L, Sor R, et al. Active RAS inhibition intercepts pancreas cancer in mice. 2026 AACR Annual Meeting. Abstract LB406/6. Presented April 21, 2026.
