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].

 

References
1. [PMID: 21993244] Pylayeva-Gupta et al. RAS oncogenes: weaving a tumorigenic web. Nat. Rev. Cancer. 2011 Oct 13;11(11):761-74. PMID: 21993244
2. [PMID: 18568040] Karnoub et al. Ras oncogenes: split personalities. Nat. Rev. Mol. Cell Biol. 2008 Jul;9(7):517-31. PMID: 18568040
3. [PMID: 27341593] Scott et al. Therapeutic Approaches to RAS Mutation. Cancer J. 2016 May-Jun;22(3):165-74. doi: 10.1097/PPO.0000000000000187. PMID: 27341593
4. [PMID: 24071849] Weinstein et al. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 2013 Oct;45(10):1113-20. PMID: 24071849
5. [PMID: 29455666] Román et al. KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer. 2018 Feb 19;17(1):33. doi: 10.1186/s12943-018-0789-x. PMID: 29455666
6. [PMID: 25713627] Dinu et al. Prognostic significance of KRAS gene mutations in colorectal cancer–preliminary study. J Med Life. 2014 Oct-Dec;7(4):581-7. PMID: 25713627
7. [PMID: 22588877] Cerami et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2012 May;2(5):401-4. PMID: 22588877
8. [PMID: 26438111] Allegra et al. Extended RAS Gene Mutation Testing in Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy: American Society of Clinical Oncology Provisional Clinical Opinion Update 2015. J. Clin. Oncol. 2016 Jan 10;34(2):179-85. PMID: 26438111
9. [FDA-sotorasib: LUMAKRAS] https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214665s000lbl.pdf
10. [FDA-adagrasib: Breakthrough] https://ir.mirati.com/press-releases/press-release-details/2021/Mirati-Therapeutics-Adagrasib-Receives-Breakthrough-Therapy-Designation-from-U.S.-Food-and-Drug-Administration-for-Patients-with-Advanced-Non-Small-Cell-Lung-Cancer-Harboring-the-KRAS-G12C-Mutation/default.aspx
11. [FDA-RO-5126766: Breakthrough] https://investor.verastem.com//news-releases/news-release-details/verastem-oncology-receives-breakthrough-therapy-designation-vs
12. [FDA-onvansertib: Fast Track] https://cardiffoncology.investorroom.com/2020-05-28-Cardiff-Oncology-Announces-Fast-Track-Designation-Granted-by-the-FDA-to-Onvansertib-for-Second-Line-Treatment-of-KRAS-Mutated-Colorectal-Cancer
13. [FDA-cetuximab: ERBITUX] https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125084s279lbl.pdf
14. [FDA-panitumumab: VECTIBIX] https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125147s210lbl.pdf
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