• What is KRAS?
  • KRAS in Colorectal Cancer
  • KRAS c.182A>C (Q61P)
  • 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/colorectal-cancer/kras/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

KRAS in Colorectal Cancer

Approximately 36–40% of patients with colorectal cancer have tumor-associated KRAS mutations (Amado et al. 2008; COSMIC; Faulkner et al. 2010Neumann et al. 2009). The concordance between primary tumor and metastases is high (Cejas et al. 2009Mariani et al. 2010; Santini et al. 2008), with only 3–7% of the tumors discordant. The majority of the mutations occur at codons 12, 13, and 61 of the KRAS gene. The result of these mutations is constitutive activation of KRAS signaling pathways.



Multiple studies have now shown that patients with tumors harboring mutations in KRAS are unlikely to benefit from anti-EGFR antibody therapy, either as monotherapy (Amado et al. 2008) or in combination with chemotherapy (Bokemeyer et al. 2009Bokemeyer et al. 2011Douillard et al. 2010Lievre et al. 2006; Peeters et al. 2010). Further, in trials of oxaliplatin based chemotherapy, the patients with KRAS mutated tumors appeared to do worse when treated with EGFR antibody therapy combined with an oxaliplatin based chemotherapy compared to the patients treated with an oxaliplatin based treatment alone.

Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2015. KRAS in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/kras/ (Updated June 18).

Last Updated: June 18, 2015

KRAS c.182A>C (Q61P) Mutation in Colorectal Cancer

Location of mutation Switch II region of the G domain (Exon 3; Ensembl; Schubbert, Shannon, and Bollag 2007)
Frequency of KRAS mutations in colorectal cancer 36–40% (Amado et al. 2008; COSMIC; Faulkner et al. 2010; Neumann et al. 2009)
Frequency of Q61P mutations among KRAS-mutated colorectal cancers < 1% (COSMIC)
Implications for Targeted Therapeutics
Response to erlotinib/gefitinib (EGFR TKIs) Unknown at this timea
Response to cetuximab/panitumumab (anti-EGFR antibodies) Confers reduced sensitivityb

The Q61P mutation results in an amino acid substitution at position 61 in KRAS, from a glutamine (Q) to a proline (P).

a Note that gefitinib monotherapy is not active in metastatic colorectal cancer (Rothenberg et al. 2005).

b Multiple studies have now shown that patients with tumors harboring mutations in KRAS or NRAS exons 2, 3, or 4 predict lack of response to anti-EGFR antibody therapy given in combination with chemotherapy (Ciardiello et al. 2014; Douillard et al. 2013; Karthaus et al. 2013; Peeters et al. 2014; Stintzing et al. 2014; Tejpar et al. 2014). In addition, patients with tumors harboring KRAS mutations are unlikely to benefit from anti-EGFR antibody monotherapy (Amado et al. 2008). While KRAS and NRAS testing are not required by the FDA, testing is recommended by NCCN (2014).

Contributors: Emily Chan, M.D., Ph.D.

Suggested Citation: Chan, E. 2017. KRAS c.182A>C (Q61P) Mutation in Colorectal Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/colorectal-cancer/kras/308/ (Updated February 16).

Last Updated: February 16, 2017

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