Combination therapy may improve treatment response in pancreatic cancer microbiologystudy

Northwestern Medicine investigators have discovered that a novel combination therapy promotes cancer cell death and tumor regression in mouse models of pancreatic cancer, according to a recent study published in the journal Cancer Research.

The findings underscore the potential of combining the KRAS inhibitor MRTX1133 with the FDA-approved drug venetoclax, commonly used to treat chronic lymphocytic leukemia and acute myeloid leukemia, as an effective treatment approach for patients with pancreatic cancer.

“We found that a combination of KRAS inhibitor, MRTX1133, and venetoclax, in fact, caused the tumors to regress. That, to me, is a clinically meaningful finding that we can take to patients. KRAS inhibitors are being considered for clinical trials, and our hope is that we can add the FDA-approved drug venetoclax to enhance the efficacy of MRTX1133,” said Hidayatullah G. Munshi, MD, ’02 GME, the Ann Lurie Professor of Hematology and Oncology and senior author of the study.

Pancreatic cancer is the third most common type of cancer in the U.S. and an estimated 66,440 cases will be diagnosed this year, according to the National Cancer Institute. Despite advances in treatment, which include surgery, radiation, chemotherapy and immunotherapy, the five-year survival rate has continued to hover around just 13%, highlighting an urgent need for more effective treatments.

The KRAS gene is an established oncogene in pancreatic cancer, and KRAS mutations are present in more than 90% of cases. More specifically, the KRASG12D mutation makes up roughly half of these cases, and while it’s an attractive therapeutic target, not all KRAS inhibitors demonstrate sustained responses in patients, according to Munshi.

“KRAS inhibitors are the new frontier in pancreatic cancer. They may have a big impact, but we also know that resistance will be inevitable. So can we do something to understand resistance mechanisms, and can we develop combination regimens?” said Munshi, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and is the newly named chief of the Division of Hematology and Oncology.

In the current study, Munshi’s team developed floating 3D collagen cultures to mimic cells in the tumor microenvironment and then treated these cells with the KRAS inhibitor drug MRTX1133.

The scientists found that while MRTX1133 increased levels of the BIM protein, which should promote cell death, the drug failed to suppress tumor cell growth or induce apoptosis.

“If the BIM protein levels increase, you expect more cell death. But in cancer cells, there’s a balance between proteins that promote cell death and those that prevent cell death. When one is trying to kill cancer cells, cells have mechanisms to prevent that from happening,” Munshi said.

To tilt the scale towards cell death, Munshi said, the scientists added the FDA-approved BCL2 inhibitor drug venetoclax to MRTX1133 and found that venetoclax enhanced the efficacy of MRTX1133 and also re-sensitized MRTX1133-resistant pancreatic cancer cells to the KRAS inhibitor. In mouse models of MRTX1133-resistant pancreatic cancer, the investigators observed cancer cell death and tumor regression.

Overall, the findings provide a rationale for testing venetoclax with KRASG12D inhibitors in pancreatic cancer patients in future clinical trials, Munshi said.

“We think that you could use this combination for increased efficacy upfront, or you could use it in a second-line setting to re-sensitize tumors to KRAS inhibitors by adding venetoclax,” Munshi said.

Thao Pham, PhD, research assistant professor of Medicine in the Division of Hematology and Oncology, was a co-author of the study.