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
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.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2015. KRAS. My Cancer
(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;
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.
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
KRAS c.34G>A (G12S) Mutation in Non-Small Cell Lung Cancer
The G12S mutation results in an amino acid substitution at position 12 in
KRAS, from a glycine (G) to a serine (S).
a The role of KRAS mutations
for selecting/prioritizing anti-cancer treatment is unknown at this time. However, it should
be noted that KRAS mutations are usually found in tumors wild type for
EGFR, ALK, and other driver mutations.
Suggested Citation: Lovly, C., L. Horn, W. Pao. 2017. KRAS c.34G>A (G12S)
Mutation in Non-Small Cell Lung Cancer. My
Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/kras/36/
(Updated February 20).
Last Updated: February 20, 2017
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