MEK and the inhibitors: from bench to bedside

Akinleye, Akintunde; Furqan, Muhammad; Mukhi, Nikhil; Ravella, Pavan Mahendra; Liu, Delong

doi:10.1186/1756-8722-6-27

Cited by 235 publications

(176 citation statements)

References 111 publications

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“…We studied the novel MEK inhibitor GDC-0623, which has been shown to have superior efficacy against KRAS compared with BRAF mutant tumors (10). We found that GDC-0623 treatment can potently up-regulate BIM and to a greater extent than observed for other MEK inhibitors that have undergone clinical evaluation (32,33). ERK silencing in GDC-0623-treated cells was shown to enhance BIM induction.…”

Section: Discussionmentioning

confidence: 98%

The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism

Zaanan

Okamoto

Kawakami

et al. 2015

Journal of Biological Chemistry

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Background: Activated KRAS-MEK/ERK signaling confers drug resistance. Results: Mutant KRAS up-regulates BCL-XL via STAT3. A MEK inhibitor induces BIM by loss of phosphorylation (Ser 69 ) and interacts synergistically with a BH3 mimetic. Conclusion: STAT3-mediated BCL-XL inhibits apoptosis in mutant KRAS cells that is overcome by a MEK inhibitor and a BH3 mimetic. Significance: STAT3-BCL-XL represents a key mechanism of apoptosis resistance by activated KRAS.

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Section: Discussionmentioning

confidence: 98%

The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism

Zaanan

Okamoto

Kawakami

et al. 2015

Journal of Biological Chemistry

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“…5 CI-1040 was the first to enter clinical trials in 2000. 2,6 Since that time, at least 13 different MEK inhibitors have been developed and evaluated in clinical trials. Recent clinical trials have used MEK inhibitors alone and in combination with other chemotherapeutic agents to treat a variety of cancers including melanoma, ovarian cancer, leukemia, lymphoma, thyroid cancer, colorectal cancer, non-small cell lung cancer, biliary cancer, and pancreatic cancer and so on.…”

Section: Literature Reviewmentioning

confidence: 99%

MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity

Duncan

Chang

Patronas

2015

Eye

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A new class of chemotherapeutic agents, MEK inhibitors, has recently been developed and is proving to be an effective treatment for a number of cancers. A pattern of ocular adverse events has followed these drugs through clinical trials and their association with retinopathy is only just beginning to be recognized. We present two cases of MEK inhibitor-associated retinopathy followed by a review of the current literature on ocular toxicity associated with MEK inhibitors. Patients undergoing treatment with MEK inhibitors appear to have high rates of multifocal serous retinal detachments as well as retinal vein occlusions. We present the first report of cystoid macular edema associated with MEK inhibitor use. The mechanism of these adverse events is still unclear though they seem to be related to oxidative stress and blood retinal barrier breakdown. Management of the ocular toxicity can range from observation to topical treatments or intravitreal injections. Fortunately most ocular adverse events appear to be selflimited and do not require discontinuing the MEK inhibitor. Discontinuation or decreased dosing of MEK inhibitors may be reserved for cases of severe sight-threatening ocular toxicity.

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“…ERK is phosphorylated by MEK proteins (also known as MAPK2K proteins) and the phosphorylation is abrogated with MEK inhibitors (Akinleye et al, 2013). We chose the widely used MEK inhibitor PD98059 to investigate the effect of abrogation of ERK phosphorylation on cell proliferation in the presence or absence of Drp1.…”

Section: The Mtcyce Pool Is Modulated By Mitochondrial Bioenergetics mentioning

confidence: 99%

A novel mitochondrial pool of Cyclin E, regulated by Drp1, is linked to cell density dependent cell proliferation

Parker

Iyer

Shah

et al. 2015

Journal of Cell Science

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The regulation and function of the crucial cell cycle regulator cyclin E (CycE) remains elusive. Unlike other cyclins, CycE can be uniquely controlled by mitochondrial energetics, the exact mechanism being unclear. Using mammalian cells (in vitro) and Drosophila (in vivo) model systems in parallel, we show that CycE can be directly regulated by mitochondria through its recruitment to the organelle. Active mitochondrial bioenergetics maintains a distinct mitochondrial pool of CycE (mtCycE) lacking a key phosphorylation required for its degradation. Loss of the mitochondrial fission protein dynaminrelated protein 1 (Drp1, SwissProt O00429 in humans) augments mitochondrial respiration and elevates the mtCycE pool allowing CycE deregulation, cell cycle alterations and enrichment of stem cell markers. Such CycE deregulation after Drp1 loss attenuates cell proliferation in low-cell-density environments. However, in high-celldensity environments, elevated MEK-ERK signaling in the absence of Drp1 releases mtCycE to support escape of contact inhibition and maintain aberrant cell proliferation. Such Drp1-driven regulation of CycE recruitment to mitochondria might be a mechanism to modulate CycE degradation during normal developmental processes as well as in tumorigenic events.

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MEK and the inhibitors: from bench to bedside

Cited by 235 publications

References 111 publications

The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism

The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism

MEK inhibitors: a new class of chemotherapeutic agents with ocular toxicity

A novel mitochondrial pool of Cyclin E, regulated by Drp1, is linked to cell density dependent cell proliferation

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