- It is a proto-oncogene that encodes a GTPase protein in the RAS/MAPK signaling pathway, which regulates cell proliferation, differentiation, and survival.
- When KRAS is mutated, it becomes constitutively active, driving uncontrolled cancer cell growth and resistance to apoptosis.
Role in Oncology
- KRAS mutations are some of the most common oncogenic drivers in solid tumors.
- They are early events in tumorigenesis and often linked to poor prognosis and treatment resistance.
Key Cancers Involving KRAS
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- KRAS mutations occur in ~40% of metastatic CRC.
- Predictive biomarker: KRAS mutations = resistance to anti-EGFR monoclonal antibodies (cetuximab, panitumumab).
- Non–small cell lung cancer (NSCLC):
- KRAS mutations in ~25–30% of adenocarcinomas.
- Subtype KRAS G12C is clinically actionable with specific inhibitors.
- Pancreatic adenocarcinoma:
- 90% harbor KRAS mutations (especially G12D, G12V).
- Drives aggressive biology, limited targeted therapy options (except clinical trials).
KRAS-Targeted Therapies
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Historically considered “undruggable,” but breakthroughs emerged:
- Other mutation-specific inhibitors (e.g., KRAS G12D inhibitors) are in clinical trials.
- Combination strategies (KRAS inhibitors + immunotherapy or other targeted agents) are under investigation.
Pharmacist’s Key Takeaway
- KRAS is a predictive biomarker: guides eligibility for EGFR inhibitors in CRC.
- KRAS mutations define therapeutic strategy in NSCLC and CRC, with targeted options available for KRAS G12C.
- Always check molecular testing results (NGS panels, PCR) to personalize therapy.
Synonyms
KRAS