RAS Inhibitor Resistance in PDAC at AACR 2025
At the AACR 2025 Annual Meeting in Chicago, Dr. Andrew Aguirre from the Dana-Farber Cancer Institute presented findings on RAS inhibitor resistance in PDAC (pancreatic ductal adenocarcinoma). This cancer type has a 5-year survival rate of 10% and is often driven by KRAS mutations, which are found in 95% of cases. Understanding resistance to RAS inhibitors is important for improving treatment outcomes in PDAC. This post summarizes the OncologyTube video covering Dr. Aguirre’s session, focusing on resistance mechanisms, challenges, and future research directions.
The Role of RAS in PDAC
RAS proteins, especially KRAS, are key drivers of PDAC tumor growth. They activate pathways such as RAF-MEK-ERK, which supports cell proliferation, and PI3K-AKT, which contributes to cell survival. When RAS inhibitors are used, resistance often develops, making treatment difficult. This resistance is a significant challenge in PDAC, where standard therapies have limited effectiveness due to the tumor’s biology.
Resistance Mechanisms to RAS Inhibitors
Dr. Aguirre, a researcher at the Dana-Farber Cancer Institute, shared a diagram of RAS inhibitor resistance in PDAC, which is detailed in the OncologyTube video:
- Activating Mutations (Green Arrows): Mutations in EGFR and HER2 can bypass RAS inhibition, allowing cancer cells to continue growing.
- Inactivating Mutations (Red Lines): Loss of PTEN increases PI3K signaling, supporting tumor survival.
- Amplifications (Blue Labels): Amplification of MET provides an alternative growth pathway.
- Transcriptional Dysregulation (Purple Labels): Dysregulation of YAP/TAZ contributes to resistance by supporting survival mechanisms.
These mechanisms enable PDAC tumors to evade RAS inhibitors, highlighting the complexity of treating this disease.
Challenges with KRAS Inhibitors in PDAC
For many years, KRAS was considered difficult to target due to its structure. Recent developments, such as the KRAS-G12C inhibitor sotorasib, have shown effectiveness in other cancers, like lung cancer, but PDAC presents ongoing challenges. Resistance to these inhibitors often develops in PDAC patients, partly because the tumor microenvironment limits immune responses. This dense stroma reduces the effectiveness of both RAS inhibitors and immunotherapies, as noted in a 2023 study published in Frontiers in Immunology.
Future Directions: Addressing RAS Inhibitor Resistance
Current research, including efforts at the Dana-Farber Cancer Institute, focuses on addressing RAS inhibitor resistance in PDAC through new strategies. Clinical trials are testing combinations of RAS inhibitors with immunotherapies to target both the tumor and its microenvironment. These studies, discussed at AACR 2025, aim to improve PDAC treatment outcomes. Researchers are also exploring new inhibitors and biomarkers to better understand and predict resistance, which could lead to more tailored treatment approaches.
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