jueves, 15 de febrero de 2018

KRAS Targeted Cancer Strategy Shows Early Promise | NIH Director's Blog

KRAS Targeted Cancer Strategy Shows Early Promise | NIH Director's Blog

KRAS Targeted Cancer Strategy Shows Early Promise

KRAS in active and inactive states
Caption: Mutant KRAS protein (white) keeps switch (red/pink) open in active state for GTP (arrow). After treatment with ARS-1620 (blue), switch is trapped in inactive GDP-bound state.
Credit: Adapted from Cell. 2018 Jan 25;172(3):578-589.
Of the more than 1.7 million Americans expected to be diagnosed with cancer this year, nearly one-third will have tumors that contain at least one mutation in the RAS family of genes [1]. That includes 95 percent of pancreatic cancers and 45 percent of colon cancers. These mutations result in the production of defective proteins that can drive cancer’s uncontrolled growth, as well as make cancers resistant to therapies. As you might expect, RAS has emerged as a major potential target for fighting cancer. Unfortunately, it is a target that’s proven very difficult to “hit” despite nearly three decades of work by researchers in both the private and public sectors, leading NIH’s National Cancer Institute to begin The RAS Initiative in 2013. This important effort has made advances with RAS that have translational potential.
Recently, I was excited to hear of progress in targeting a specific mutant form of KRAS, which is a protein encoded by a RAS gene involved in many lung cancers and some pancreatic and colorectal cancers. The new study, carried out by a pharmaceutical research team in mouse models of human cancer, is the first to show that it is possible to shrink a tumor in a living creature by directly inhibiting mutant KRAS protein [2].
First, a primer on KRAS: In healthy cells, the protein relays key signals from the cell surface to the nucleus. Those signals determine whether a cell continues growing or stops dividing as it differentiates and matures.
To get the growth signals right, KRAS works much like an on-off switch. At the biochemical level, the switch is toggled “on” by the binding of a small molecule called GTP. Normal KRAS protein then converts GTP to another molecule called GDP, turning itself back “off.” But in some cancer cells, the “off” switch doesn’t work. A gene mutation leads to a misshaped KRAS protein that can’t convert GTP to GDP. This causes the switch to stay stuck in the “on” position, fueling the cancer cell’s abnormal growth.
A drug capable of switching “off” the KRAS protein would clearly hold promise in fighting cancer. But there’s been a seemingly intractable problem: the protein binds GTP with incredible specificity. As hard as they’ve worked, researchers can’t seem to find the right small molecule that can horn in and block that interaction.
In addition, targeted small molecules usually work by reversibly binding to pockets found at the surface of a target protein. But KRAS had seemed to lack pockets suitable for binding with sufficient strength.
Recently, scientists grew hopeful of developing drugs designed to target specific KRAS mutations that are important in many cancers [3]. In fact, earlier studies in cells grown in lab dishes showed that a small molecule could permanently bind a particular mutant form of the protein called KRASG12C [4-6].. The mutation involves a single amino acid substitution at position 12 in KRAS, from a glycine (G) to a cysteine (C).
Those small molecules work by forming covalent chemical bonds with inactive KRASG12C proteins. They trap KRAS in that non-functional state before it can get stuck in the “on” position to fuel a tumor’s abnormal growth.
In a recent study in the journal Cell,  researchers led by Yi Liu at Wellspring Biosciences, San Diego, first worked to improve the earlier developed compound. They now show that their new compound, called ARS-1620, is 10 times more effective in chemically modifying KRASG12C proteins in cancer cells than the one tested previously. But a big question remained: would it work in a living creature?
To find out, the researchers gave oral doses of ARS-1620 to mice that had human cancers carrying the KRASG12C mutation grafted under their skin. They found that the drug reached the tumor after a single dose and increased in concentration after five consecutive daily doses. But more importantly: the treatment, given once daily for a period of three weeks, led to a significant reduction in tumor growth. ARS-1620 treatment was also well tolerated by the mice, with no signs of toxicity even when given in relatively high daily doses. As anticipated, animals whose tumors lacked KRASG12C didn’t respond to the treatment.
The findings appear to make ARS-1620 the very first KRASG12C inhibitor that’s potent, selective, and capable of reaching a tumor when taken orally. That’s encouraging because the G12C mutation is found in up to 16 percent of non-small cell lung cancers and 1 to 4 percent of pancreatic and colorectal cancers, which are tumors that currently lack targeted treatment options. With proof-of-concept in cells and animal models now established, the hope is that further study of such a compound will ultimately show promise in treating human cancers.
[1] Cancer Facts and Figures 2018. The American Cancer Society.
[2] Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. Janes MR, Zhang J, Li LS, Hansen R, Peters U, Guo X, Chen Y, Babbar A, Firdaus SJ, Darjania L, Feng J, Chen JH, Li S, Li S, Long YO, Thach C, Liu Y, Zarieh A, Ely T, Kucharski JM, Kessler LV, Wu T, Yu K, Wang Y, Yao Y, Deng X, Zarrinkar PP, Brehmer D, Dhanak D, Lorenzi MV, Hu-Lowe D, Patricelli MP, Ren P, Liu Y. Cell. 2018 Jan 25;172(3):578-589.
[3] Mutation-Specific Approaches to KRAS Cancers: What We Can Learn from G12C-Directed Inhibitors. Sharon Campbell. National Cancer Institutes’s The RAS Initiative. 2016 Jan 12.
[4] Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism. Lito P, Solomon M, Li LS, Hansen R, Rosen N. Science. 2016 Feb 5;351(6273):604-8.
[5] Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State. Patricelli MP, Janes MR, Li LS, Hansen R, Peters U, Kessler LV, Chen Y, Kucharski JM, Feng J, Ely T, Chen JH, Firdaus SJ, Babbar A, Ren P, Liu Y. Cancer Discov. 2016 Mar;6(3):316-29.
[6] K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. Nature. 2013 Nov 28;503(7477):548-551.
The RAS Initiative (National Cancer Institute/NIH)
NIH Support: National Cancer Institute

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