• What is KRAS?
  • KRAS in Colorectal Cancer
  • KRAS Wild Type
  • Clinical Trials

KRAS

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. 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 review see Schubbert, Shannon, and Bollag 2007).

mapk-pk13.png

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.

Contributors: Christine Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D.

Last Updated: June 5, 2012

KRAS Mutations in Colorectal Cancer

Approximately 40% of patients with colorectal cancer have tumor-associated KRAS mutations (Amado et al. 2008Faulkner 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.

Last Updated: June 1, 2012

KRAS Wild Type in Colorectal Cancer

Properties
Location of mutation N/A
Frequency 60% of all colorectal cancers
Implications for Targeted Therapeutics
Response to erlotinib/gefitinib (EGFR TKIs) Unknown at this time. However, gefitinib monotherapy is not active in metastatic colorectal cancer (Rothenberg et al. 2005)
Response to cetuximab, panitumumab (anti-EGFR antibodies) Possible

Approximately 60% of all colorectal cancers contain wild type KRAS (no mutation detected in the KRAS gene).

Multiple studies have shown that patients with tumors harboring wild type KRAS may 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; Van Cutsem et al. 2011). Combining an anti-EGFR antibody with chemotherapy increases the response rate and progression free survival over anti-EGFR antibody therapy alone (Bokemeyer et al. 2009; Douillard et al. 2010; Peeters et al. 2010; Van Cutsem et al. 2011).

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

Last Updated: June 1, 2012

KRAS-Associated Colorectal Cancer Clinical Trials

Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.

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