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RAS and Other Molecular Targets in Pancreatic Cancer: The Next Wave Is Coming
Lisa Miller-Phillips1, Eric A Collisson2
1Division of Hematology and Oncology, Department of Medicine and Helen Diller Family Comprehensive Cancer Center, UCSF, 1450 3Rd Street HD-375, San Francisco, CA, 94158-0128, USA.
Opinion Statement:
Since the discovery of oncogenes in the 1970s, cancer doctors and researchers alike have understood the promise of discovering drugs to block the dominantly acting function of mutated signaling proteins in cancer. This promise was delivered, first slowly, with early signals inhibiting HER2 and BCR-Abl in the 1990s and 2000s, and then quickly, with kinase inhibitors being approved hand over fist in non-small cell lung cancer, melanoma, and many other malignancies. The RAS proteins, however, remained recalcitrant to chemical inhibition for decades, despite being, by far, the most frequently mutated oncogenes in cancers of all types. Nowhere was this deficit more palpable than in pancreatic ductal adenocarcinoma (PDA), where > 90% of cases are driven by single nucleotide substitutions at a single codon of the KRAS gene. The ice began to crack in 2012 when Ostrem and colleagues (Nature 503(7477): 548-551, 2013) synthesized the first KRAS G12C inhibitors, which covalently bind to GDP-bound G12C-mutated KRAS and lock the oncoprotein in its inactive state. In the last decade, the scientific community has established a new foundation on this and other druggable pockets in mutant KRAS. Here we provide an up-to-date overview of drugs targeting KRAS and other molecular targets in pancreatic cancer.
Insights
Targeting mutated KRAS proteins, especially in pancreatic cancer, has been a long-standing challenge. Recent advances have led to the development of novel KRAS inhibitors, offering new hope for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Oncogene discovery in the 1970s highlighted the potential for targeted cancer therapies.
- Early successes included inhibitors for HER2 and BCR-Abl, followed by numerous kinase inhibitors.
- RAS proteins, frequently mutated in cancer, were historically difficult to inhibit directly.
Purpose of the Study:
- To provide an updated overview of drugs targeting KRAS mutations in cancer.
- To discuss the challenges and progress in developing KRAS-specific inhibitors.
- To highlight therapeutic strategies for pancreatic ductal adenocarcinoma (PDA) driven by KRAS mutations.
Main Methods:
- Review of scientific literature on KRAS inhibitors and targeted cancer therapies.
- Analysis of historical and recent developments in oncogene-targeted drug discovery.
- Focus on KRAS G12C inhibitors and their mechanism of action.
Main Results:
- The development of KRAS inhibitors has overcome previous challenges in targeting these oncogenes.
- KRAS G12C inhibitors, developed since 2012, covalently bind and inactivate the mutated protein.
- Significant progress has been made in establishing a foundation for targeting mutant KRAS in various malignancies.
Conclusions:
- Targeting KRAS mutations represents a significant advancement in cancer therapy.
- KRAS inhibitors hold promise for treating cancers, particularly pancreatic cancer with high KRAS mutation rates.
- Continued research is expanding the landscape of molecularly targeted drugs for pancreatic cancer.
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