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Targeting KRAS in pancreatic cancer
Sandra Stickler1, Barbara Rath1, Gerhard Hamilton1
1Institute of Pharmacology, Medical University of Vienna, Vienna, A-1090, Austria.
Abstract:
Pancreatic cancer has a dismal prognosis due to late detection and lack of efficient therapies. The Kirsten rat sarcoma virus (KRAS) oncogene is mutated in up to 90% of all pancreatic ductal adenocarcinomas (PDACs) and constitutes an attractive target for therapy. However, the most common KRAS mutations in PDAC are G12D (44%), G12V (34%) and G12R (20%) that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer. KRAS G12C mutant pancreatic cancer has been treated with Sotorasib but this mutation is detected only in 2%-3% of PDAC. Recently, the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development. The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor (GEF) Son of Sevenless 1 that drives KRAS. These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.
Insights
New KRAS inhibitors target common pancreatic cancer mutations. Emerging therapies like MRTX1133 and GEF inhibitors offer hope for treating pancreatic ductal adenocarcinoma (PDAC) by addressing prevalent KRAS mutations.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), has a poor prognosis due to late detection and limited therapeutic options.
- The Kirsten rat sarcoma virus (KRAS) oncogene is frequently mutated in PDAC (up to 90%), making it a key therapeutic target.
Purpose of the Study:
- To review the challenges and advancements in targeting KRAS mutations in pancreatic cancer.
- To highlight novel therapeutic strategies for prevalent KRAS mutations in PDAC.
Main Methods:
- Analysis of current literature on KRAS mutations in PDAC.
- Review of emerging KRAS-targeted therapies and indirect inhibition strategies.
Main Results:
- Common KRAS mutations in PDAC (G12D, G12V, G12R) are not targeted by existing KRAS G12C inhibitors like Sotorasib.
- KRAS G12C mutations, though targetable, are rare in PDAC (2-3%).
- New inhibitors like MRTX1133 targeting KRAS G12D are in clinical trials, and indirect targeting via Son of Sevenless 1 (SOS1) inhibition is under development.
Conclusions:
- Emerging KRAS-directed therapies and indirect targeting strategies show promise for addressing the most common KRAS mutations in PDAC.
- These novel approaches have the potential to significantly improve treatment outcomes for pancreatic cancer patients.
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