Reference Detail

Ref Type

Journal Article

PMID

(26037647)

Authors

Hunter JC, Manandhar A, Carrasco MA, Gurbani D, Gondi S, Westover KD

Title

Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer research : MCR	13	9	2015 Sep	1325-35	Mol Cancer Res

URL

Abstract Text

KRAS mutations are the most common genetic abnormalities in cancer, but the distribution of specific mutations across cancers and the differential responses of patients with specific KRAS mutations in therapeutic clinical trials suggest that different KRAS mutations have unique biochemical behaviors. To further explain these high-level clinical differences and to explore potential therapeutic strategies for specific KRAS isoforms, we characterized the most common KRAS mutants biochemically for substrate binding kinetics, intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activities, and interactions with the RAS effector, RAF kinase. Of note, KRAS G13D shows rapid nucleotide exchange kinetics compared with other mutants analyzed. This property can be explained by changes in the electrostatic charge distribution of the active site induced by the G13D mutation as shown by X-ray crystallography. High-resolution X-ray structures are also provided for the GDP-bound forms of KRAS G12V, G12R, and Q61L and reveal additional insight. Overall, the structural data and measurements, obtained herein, indicate that measurable biochemical properties provide clues for identifying KRAS-driven tumors that preferentially signal through RAF.Biochemical profiling and subclassification of KRAS-driven cancers will enable the rational selection of therapies targeting specific KRAS isoforms or specific RAS effectors.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
NRAS	G12A	missense	loss of function - predicted	NRAS G12A is hotspot mutation that lies within a GTP-binding region of the Nras protein (UniProt.org). G12A has not been characterized, but can be predicted to confer a loss of function to the Nras protein based on the effects of HRAS G12A and KRAS G12A, which results in decreased GTPase activity, loss of response to GTPase-activating proteins, and transformation of cultured cells (PMID: 6092966, PMID: 26037647).
NRAS	G12C	missense	loss of function - predicted	NRAS G12C is a hotspot mutation that lies within a GTP-binding region of the Nras protein (UniProt.org). G12C has not been characterized, but can be predicted to confer a loss of function to the Nras protein based on the effects of HRAS G12C and KRAS G12C, which result in a loss of response to GTPase-activating proteins, and transformation of cultured cells (PMID: 26037647, PMID: 6092966).
NRAS	Q61L	missense	loss of function - predicted	NRAS Q61L is a hotspot mutation that lies within a GTP-binding region of the Nras protein (UniProt.org). Q61L results in increase Erk and Mek phosphorylation, and activation of Ck2alpha in cell culture (PMID: 27251789), and is predicted to lead to a loss of Nras protein function based on the effects of HRAS Q61L (PMID: 23487764) and KRAS Q61L (PMID: 26037647).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References