{"id":4790,"date":"2019-11-11T13:59:09","date_gmt":"2019-11-11T04:59:09","guid":{"rendered":"http:\/\/163.180.4.222\/lab\/?p=4790"},"modified":"2019-11-11T13:59:09","modified_gmt":"2019-11-11T04:59:09","slug":"small-molecule-combats-cancer-causing-kras-protein-at-last","status":"publish","type":"post","link":"https:\/\/biochemistry.khu.ac.kr\/lab\/?p=4790","title":{"rendered":"Small molecule combats cancer-causing KRAS protein at last"},"content":{"rendered":"

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A molecule has now been characterized that acts to inhibit a cancer-causing form of KRAS protein and stimulate the immune system. The inhibitor is one of the first of its kind to show anticancer activity in the clinic.<\/h5>\n

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Mutations in the gene\u00a0KRAS<\/i>\u00a0are the most frequent drivers of tumour development across the spectrum of human cancers1<\/a><\/sup>. Despite this prevalence, mutant KRAS protein has remained an intractable therapeutic target.\u00a0Writing in\u00a0Nature<\/i><\/a>, Canon\u00a0et al.<\/i>2<\/a><\/sup>\u00a0describe a small molecule that binds one form of mutant KRAS with high specificity and sensitivity, inhibiting the protein. The authors use animal models to analyse how the inhibitor works, and show that it can shrink tumours in patients. This is among the first evidence of a clinical response to a specific KRAS inhibitor.<\/p>\n

KRAS is an enzyme that controls a signalling pathway crucial for cell growth, differentiation and survival. The inactive protein is bound by a guanosine diphosphate (GDP) molecule \u2014 replacement of GDP by guanosine triphosphate (GTP) facilitates conformational changes in KRAS that allow the enzyme to bind and activate downstream effector molecules (Fig. 1a). Nearly all cancer-promoting KRAS mutations prevent GTP breakdown, leaving KRAS in a permanently active state3<\/a><\/sup>\u00a0(Fig. 1b). One such mutation involves substitution of a glycine amino-acid residue for a cysteine residue. The resulting mutant protein, KRASG12C<\/sup>, is found infrequently in various cancers. It is most prevalent in lung cancer, and is responsible for approximately 12% of non-small cell lung cancers4<\/a><\/sup>,<\/sup>5<\/a><\/sup>.<\/p>\n

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Figure 1 | Inhibitor blocks the action of a mutant KRAS protein.<\/b>\u00a0a<\/b>, KRAS is activated in normal tissues by replacement of a bound guanosine diphosphate (GDP) molecule with guanosine triphosphate (GTP). This exchange leads to conformational changes in KRAS, to binding of the protein Raf and so to activation of downstream signalling pathways that control cell growth and differentiation. GTP is broken down to GDP to inactivate KRAS once more.\u00a0b<\/b>, A mutant form of KRAS, dubbed KRASG12C<\/sup>, prevents GTP breakdown, rendering the protein permanently active \u2014 this, in turn, can lead to cancer.\u00a0c<\/b>, Canon\u00a0et al.<\/i>2<\/a><\/sup>\u00a0have characterized a small molecule, AMG 510, that interacts with KRASG12C<\/sup>\u00a0to prevent GTP binding in the first place, thus inhibiting the protein\u2019s cancer-promoting activity.<\/span><\/p>\n<\/figcaption><\/figure>\n

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In the past few years, several irreversible small-molecule inhibitors have been developed6<\/a><\/sup>\u2013<\/sup>8<\/a><\/sup>\u00a0that bind covalently to a pocket in GDP\u2011bound KRASG12C<\/sup>\u00a0to inhibit GTP binding. These inhibitors successfully prevent activation of the protein in animal models, but none has had any effect on tumours in patients. Canon\u00a0et al.<\/i>\u00a0characterized another small-molecule inhibitor, AMG 510, that forms a covalent bond with GDP\u2011bound KRASG12C<\/sup>\u00a0(Fig. 1c). AMG 510 has similar structural properties to one of the previous inhibitors, ARS-1620, but has one key difference \u2014 it binds a structure called a cryptic surface groove that forms in KRASG12C<\/sup>, and so recognizes the mutant protein with high specificity.<\/p>\n

The authors showed that AMG 510 inhibits the exchange of GDP for GTP more potently than does ARS-1620. Moreover, AMG 510 strongly inhibits phosphorylation of the protein ERK (a known effector of KRAS activity) in cells harbouring KRASG12C<\/sup>, and impairs cell proliferation.<\/p>\n

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