Venetoclax Enhances KRAS Inhibitor Efficacy in Pancreatic Cancer Models

• Combination therapy of MRTX1133 and venetoclax induces cancer cell death and tumor regression in pancreatic cancer mouse models, suggesting clinical potential.
• The KRAS inhibitor MRTX1133 increases BIM protein levels, but fails to suppress tumor growth, necessitating the addition of venetoclax to promote cell death.
• Venetoclax re-sensitizes MRTX1133-resistant pancreatic cancer cells to the KRAS inhibitor, offering a strategy for overcoming resistance in patients.
• The findings support clinical trials testing venetoclax with KRASG12D inhibitors for pancreatic cancer, potentially improving treatment efficacy upfront or in second-line settings.

Northwestern Medicine investigators have discovered that combining the KRAS inhibitor MRTX1133 with venetoclax, an FDA-approved BCL2 inhibitor, promotes cancer cell death and tumor regression in mouse models of pancreatic cancer. The study, published in Cancer Research, suggests a promising new treatment approach for this challenging disease.

Targeting KRAS and BCL2 for Enhanced Efficacy

The KRAS gene is a well-established oncogene in pancreatic cancer, with mutations present in over 90% of cases. Specifically, the KRASG12D mutation accounts for approximately half of these cases. While KRAS inhibitors represent a new frontier in pancreatic cancer treatment, resistance remains a significant challenge. Hidayatullah G. Munshi, MD, the Ann Lurie Professor of Hematology and Oncology and senior author of the study, noted the importance of developing combination regimens to overcome resistance mechanisms.

Overcoming Resistance Mechanisms

In the study, the team developed 3D collagen cultures to mimic the tumor microenvironment and treated these cells with MRTX1133. They found that while MRTX1133 increased levels of the BIM protein, which should promote cell death, the drug alone failed to suppress tumor cell growth or induce apoptosis. To address this, the scientists added venetoclax, an FDA-approved BCL2 inhibitor, to MRTX1133. The combination enhanced the efficacy of MRTX1133 and 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.

Clinical Implications and Future Directions

These findings provide a rationale for testing venetoclax with KRASG12D inhibitors in pancreatic cancer patients in future clinical trials. According to Munshi, this combination could be used for increased efficacy upfront or in a second-line setting to re-sensitize tumors to KRAS inhibitors by adding venetoclax. Given the poor five-year survival rate of approximately 13% for pancreatic cancer, novel therapeutic strategies are urgently needed. This combination approach offers a potential avenue for improving outcomes in patients with KRAS-mutated pancreatic cancer.