KRAS
Kirsten rat sarcoma viral oncogene homologue (KRAS)
KRAS Biology
KRAS was first detected in 1982 in lung cancer cells, located on the short arm of chromosome 12 (12p11.1–12p12.1).1 KRAS is a member of the RAS family of GTPase signal transducer proteins which include Harvey rat sarcoma viral oncogene (HRAS) and neuroblastoma rat sarcoma oncogene (NRAS). These proteins hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP) and serve as molecular switches that cycle between the inactive GDP-bound state and the active GTP-bound state under normal conditions. When active, KRAS activates the MAPK and PI3K signaling pathways that promote cell proliferation, growth, and survival.2
KRAS is a commonly occurring oncogene with the highest mutation rate among all cancers, and mutated forms of KRAS (more frequent in patients with a smoking history) are present in approximately 25% of lung adenocarcinomas.3 Alterations in KRAS are an early event in lung tumorigenesis. They are associated with a history of smoking4,5, a high mutation burden, and elevated markers of immune evasion (PD-L1 and PD-L2).6 Most mutations occur in exons 2 or 3, resulting in impaired GTPase activity. Approximately 42% of mutations result in substitution of cysteine for glycine at codon 12 (G12C; in exon 2).7 These alterations result in an isoform that inhibits GTP hydrolysis and locks G12C-mutant KRAS in its active state. This, in turn, causes constitutive activation of the MAPK and PI3K pathways, thereby promoting tumorigenesis.2 While KRAS G12C mutations are the most common, accounting for 40% of KRAS mutations in NSCLC, there are several relevant mutations including KRAS G12V (19%) and KRAS G12D (15%).8
KRAS Testing
The KRAS alteration relevant in NSCLC is mutation vs amplification or expression. As the majority of lung cancers are detected at an advanced stage, biomarker testing should be performed as soon as possible. Next-generation sequencing (NGS), real-time polymerase chain reaction (PCR), and Sanger sequencing (ideally paired with tumor enrichment) are the most commonly deployed methodologies for examining alterations in KRAS. When feasible, a broad, panel-based approach, most typically performed by NGS, is recommended by the NCCN.9 The specific KRAS mutation is important as the currently available agents are designed specifically for KRAS G12C.10
KRAS Targeted Therapy
Two oral medications have been approved by the US Food & Drug Administration (FDA) for treatment of KRAS G12C-mutated locally advanced or metastatic NSCLC: sotorasib in 2021 and adagrasib in 2022. Both drugs have the similar mechanism of action, namely that they selectively and irreversibly bind to cysteine 12 in KRAS and lock it in its inactive state.11
References
1. Chang EH, Gonda MA, Ellis RW, et al. Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. Proc Natl Acad Sci USA 1982; 79:4848–4852. doi:10.1073/pnas.79.16.4848
2. O’Sullivan É, Keogh A, Henderson B, et al. Treatment strategies for KRAS-mutated non-small-cell lung cancer. Cancers (Basel). 2023; 15(6):1635. doi:10.3390/cancers15061635
3. Tsao AS, Scagliotti GV, Bunn PA Jr, et al. Scientific advances in lung cancer 2015. J Thorac Oncol. 2016; 11:613-638. doi:10.1016/j.jtho.2016.03.012
4. Westra WH, Baas IO, Hruban RH, et al. K-ras oncogene activation in atypical alveolar hyperplasias of the human lung. Cancer Res. 1996;56(9):2224-2228.
5. Riely GJ, Kris MG, Rosenbaum D, et al. Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res. 2008; 14:5731–5734. doi:10.1158/1078-0432.CCR-08-0646
6. Calles A, Liao X, Sholl LM, et al. Expression of PD-1 and its ligands, PD-L1 and PD-L2, in smokers and never smokers with KRAS-mutant lung cancer. J Thorac Oncol. 2015; 10:1726–1735. doi:10.1097/JTO.0000000000000687
7. Karachaliou N, Mayo C, Costa C, et al. KRAS mutations in lung cancer. Clin Lung Cancer. 2013; 14:205-214. doi:10.1016/j.cllc.2012.09.007
8. Judd J, Abdel Karim N, Khan H, Naqash AR, et al. Characterization of KRAS mutation subtypes in non-small cell lung cancer. Mol Cancer Ther. 2021;20(12):2577-2584. doi:10.1158/1535-7163.MCT-21-0201
9. National Comprehensive Cancer Network. NCCN guidelines version 2.2024: Non-Small Cell Lung Cancer. Accessed May 17, 2024.
10. Shim HS, Kenudson M, Zheng Z, et al. Unique genetic and survival characteristics of invasive mucinous adenocarcinoma of the lung. J Thorac Oncol. 2015; 10:1156–1162. doi:10.1097/JTO.0000000000000579
11. Veluswamy R, Mack PC, Houldsworth J, et al. KRAS G12C-mutant non-small cell lung cancer: biology, developmental therapeutics, and molecular testing. J Mol Diagn. 2021; 23:507–520. doi:10.1016/j.jmoldx.2021.02.002
Additional Reading
Amanam I, Mambetsariev I, Gupta R, Achuthan S, Wang Y, Pharaon R, Massarelli E, Koczywas M, Reckamp K, Salgia R. Role of immunotherapy and co-mutations on KRAS-mutant non-small cell lung cancer survival. J Thorac Dis. 2020; 12(9):5086–5095. doi:10.21037/jtd.2020.04.18
Lim TKH, Skoulidis F, Kerr KM, et al. KRAS G12C in advanced NSCLC: Prevalence, co-mutations, and testing. Lung Cancer. 2023; 184:107293. doi:10.1016/j.lungcan.2023.107293
Salgia R, Pharaon R, Mambetsariev I, et al. The improbable targeted therapy: KRAS as an emerging target in non-small cell lung cancer (NSCLC). Cell Rep Med. 2021; 2(1):100186. doi:10.1016/j.xcrm.2020.100186
