• What is KRAS?
  • KRAS in Lung Cancer
  • Clinical Trials


Three different human RAS genes have been identified: KRAS (homologous to the oncogene from the Kirsten rat sarcoma virus), HRAS (homologous to the oncogene from the Harvey rat sarcoma virus), and NRAS (first isolated from a human neuroblastoma). The different RAS genes are highly homologous but functionally distinct; the degree of redundancy remains a topic of investigation (reviewed in Pylayeva-Gupta et al. 2011). RAS proteins are small GTPases which cycle between inactive guanosine diphosphate (GDP)-bound and active guanosine triphosphate (GTP)-bound forms. RAS proteins are central mediators downstream of growth factor receptor signaling and therefore are critical for cell proliferation, survival, and differentiation. RAS can activate several downstream effectors, including the PI3K-AKT-mTOR pathway, which is involved in cell survival, and the RAS-RAF-MEK-ERK pathway, which is involved in cell proliferation (Figure 1).

RAS has been implicated in the pathogenesis of several cancers. Activating mutations within the RAS gene result in constitutive activation of the RAS GTPase, even in the absence of growth factor signaling. The result is a sustained proliferation signal within the cell.

Specific RAS genes are recurrently mutated in different malignancies. KRAS mutations are particularly common in colon cancer, lung cancer, and pancreatic cancer (for reviews see Karnoub and Weinberg 2008 and Schubbert, Shannon, and Bollag 2007).


Figure 1.
Schematic of the MAPK and PI3K pathways. Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. KRAS. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/kras/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

KRAS in Non-Small Cell Lung Cancer (NSCLC)

Approximately 15–25% of patients with lung adenocarcinoma have tumor associated KRAS mutations. KRAS mutations are uncommon in lung squamous cell carcinoma (Brose et al. 2002). In the majority of cases, these mutations are missense mutations which introduce an amino acid substitution at position 12, 13, or 61. The result of these mutations is constitutive activation of KRAS signaling pathways.

In the vast majority of cases, KRAS mutations are found in tumors wild type for EGFR or ALK​; in other words, they are non-overlapping with other oncogenic mutations found in NSCLC. Therefore, KRAS mutation defines a distinct molecular subset of the disease. KRAS mutations are found in tumors from both former/current smokers and never smokers. They are rarer in never smokers and are less common in East Asian vs. US/European patients (Riely et al. 2008; Sun et al. 2010).

The role of KRAS as either a prognostic or predictive factor in NSCLC is unknown at this time. Very few prospective randomized trials have been completed using KRAS as a biomarker to stratify therapeutic options in the metastatic setting. Unlike in colon cancer, KRAS mutations have not yet been shown in NSCLC to be negative predictors of benefit to anti-EGFR antibodies. However, KRAS mutations are negative predictors of radiographic response to the EGFR tyrosine kinase inhibitors, erlotinib and gefitinib [for review, see (Riely and Ladanyi 2008; Riely, Marks, and Pao 2009)]. Currently, there are no direct anti-KRAS therapies available.

Contributors: Christine M. Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. KRAS in Non-Small Cell Lung Cancer (NSCLC). My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/kras/ (Updated June 18).

Last Updated: June 18, 2015

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