KRAS Mutation Analysis by PCR

Clinical Significance
The KRAS proto-oncogene encodes a GTPase that functions in signal transduction and is a member of the RAS superfamily which also includes NRAS and HRAS. RAS proteins mediate the transmission of growth signals from the cell surface to the nucleus via the PI3K/AKT/MTOR and RAS/RAF/MEK/ERK pathways, which regulate cell division, differentiation, and survival [PMID: 21993244;PMID: 18568040;PMID: 27341593]. Recurrent mutations in RAS oncogenes cause constitutive activation and are found in 20-30% of cancers. KRAS mutations are observed in up to 10-20% of uterine cancer, 30-35% of lung adenocarcinoma and colorectal cancer, and about 60% of pancreatic cancer [PMID: 24071849]. The majority of KRAS mutations consist of point mutations occurring at G12, G13, and Q61[PMID: 24071849;PMID: 29455666;PMID: 25713627]. Mutations at A59, K117, and A146 have also been observed but are less frequent [PMID: 22588877;PMID: 26438111].
The KRAS inhibitor, sotorasib[FDA-sotorasib: LUMAKRAS], is approved (2021) for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). The FDA has granted breakthrough therapy designation (2021) to the small molecule inhibitor, adagrasib, for KRAS G12C positive in non-small cell lung cancer following prior systemic therapy[FDA-adagrasib: Breakthrough].The small molecular inhibitor, RO-5126766, was also granted breakthrough designation (2021) alone for KRAS G12V mutant non-small cell lung cancer or in combination with defactinib, for KRAS mutant endometrial carcinoma and KRAS G12V mutant non-small cell lung cancer[FDA-RO-5126766: Breakthrough]. Additionally, onvansertib[FDA-onvansertib: Fast Track] was granted fast track designation (2020) for second-line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC). The EGFR antagonists, cetuximab[FDA-cetuximab: ERBITUX] and panitumumab[FDA-panitumumab: VECTIBIX], are contraindicated for treatment of colorectal cancer patients with KRAS mutations in exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146)[PMID: 26438111]. Additionally, KRAS mutations are associated with poor prognosis in NSCLC[PMID: 2199829].


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9. [FDA-sotorasib: LUMAKRAS]
10. [FDA-adagrasib: Breakthrough]
11. [FDA-RO-5126766: Breakthrough]
12. [FDA-onvansertib: Fast Track]
13. [FDA-cetuximab: ERBITUX]
14. [FDA-panitumumab: VECTIBIX]
15. [PMID: 2199829] Slebos et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N. Engl. J. Med. 1990 Aug 30;323(9):561-5. PMID: 2199829