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Not just gRASping at flaws: finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers.

Ebi H, Faber AC, Engelman JA, Yano S - Cancer Sci. (2014)

Bottom Line: Mutations in Kirsten rat-sarcoma (KRAS) are well appreciated to be major drivers of human cancers through dysregulation of multiple growth and survival pathways.Similar to many other non-kinase oncogenes and tumor suppressors, efforts to directly target KRAS pharmaceutically have not yet materialized.Fueling these efforts is our increased understanding into the biology driving KRAS mutant cancers, in particular the important pathways that mutant KRAS governs to promote survival.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.

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Effector pathways of Kirsten rat-sarcoma (KRAS). Proteins highlighted green are pharmacologically targetable.
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fig01: Effector pathways of Kirsten rat-sarcoma (KRAS). Proteins highlighted green are pharmacologically targetable.

Mentions: Kirsten rat-sarcoma protein cycles between an inactive GDP-bound state and an active GTP-bound state. A number of stimuli, including ligands that activate growth factor receptors and G-protein coupled receptors on the cell membrane, lead to the activation of RAS guanine exchange factors (GEFs).6 This, in turn, results in the formation of active GTP-bound KRAS. In wild-type KRAS cells, KRAS is subsequently inactivated by Ras-GTPase activating proteins (RasGAPs). However, oncogenic KRAS mutations, which occur most frequently at amino acids 12, 13, and 61, render KRAS proteins resistant to RasGAP-mediated GTP-hydrolysis. This leads to constitutive activation of KRAS protein. Mutant KRAS activates multiple downstream effector pathways, resulting in the uncontrolled growth, proliferation, and survival of cancer cells (Fig.1). Amongst these, three major effector pathways have emerged as being critical to mutant KRAS-mediated transformation and will be discussed in greater detail: the RAF-MEK-ERK pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, and the Ral-NF-kB pathway.


Not just gRASping at flaws: finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers.

Ebi H, Faber AC, Engelman JA, Yano S - Cancer Sci. (2014)

Effector pathways of Kirsten rat-sarcoma (KRAS). Proteins highlighted green are pharmacologically targetable.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317830&req=5

fig01: Effector pathways of Kirsten rat-sarcoma (KRAS). Proteins highlighted green are pharmacologically targetable.
Mentions: Kirsten rat-sarcoma protein cycles between an inactive GDP-bound state and an active GTP-bound state. A number of stimuli, including ligands that activate growth factor receptors and G-protein coupled receptors on the cell membrane, lead to the activation of RAS guanine exchange factors (GEFs).6 This, in turn, results in the formation of active GTP-bound KRAS. In wild-type KRAS cells, KRAS is subsequently inactivated by Ras-GTPase activating proteins (RasGAPs). However, oncogenic KRAS mutations, which occur most frequently at amino acids 12, 13, and 61, render KRAS proteins resistant to RasGAP-mediated GTP-hydrolysis. This leads to constitutive activation of KRAS protein. Mutant KRAS activates multiple downstream effector pathways, resulting in the uncontrolled growth, proliferation, and survival of cancer cells (Fig.1). Amongst these, three major effector pathways have emerged as being critical to mutant KRAS-mediated transformation and will be discussed in greater detail: the RAF-MEK-ERK pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, and the Ral-NF-kB pathway.

Bottom Line: Mutations in Kirsten rat-sarcoma (KRAS) are well appreciated to be major drivers of human cancers through dysregulation of multiple growth and survival pathways.Similar to many other non-kinase oncogenes and tumor suppressors, efforts to directly target KRAS pharmaceutically have not yet materialized.Fueling these efforts is our increased understanding into the biology driving KRAS mutant cancers, in particular the important pathways that mutant KRAS governs to promote survival.

View Article: PubMed Central - PubMed

Affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.

Show MeSH
Related in: MedlinePlus