MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives

Ram, Thomas Samuel; Singh, Ankit Kumar; Kumar, Adarsh; Singh, Harshwardhan; Pathak, Prateek; Grishina, Maria; Khalilullah, Habibullah; Poulson, Benjamin Gabriel; Emwas, Abdul‐Hamid; Verma, Amita; Kumar, Pradeep

doi:10.1039/d3md00145h

Cited by 5 publications

(1 citation statement)

References 158 publications

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“…More recently, dupilumab has been reported as an off-label treatment for refractory GD (58-60), though its blockade of interleukin-4 and -13 receptors may target secondary pruritus and inflammation rather than the primary pathogenic drivers of GD. Our findings suggest MEK inhibitors, which are FDA-approved for oral administration for multiple BRAF -driven cancers (17, 61-65), could be therapeutic for GD as well as Darier disease. Moreover, MEK inhibitors can be delivered topically as shown by successful use of compounded trametinib to treat a cutaneous histiocyte proliferation driven by MAP kinase overactivation (66).…”

Section: Discussionmentioning

confidence: 77%

ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology

Simpson,

Tiwaa,

Zaver

et al. 2024

Preprint

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Grover disease is an acquired dermatologic disorder characterized by pruritic vesicular and eroded skin lesions. While its pathologic features are well-defined, including impaired cohesion of epidermal keratinocytes, the etiology of Grover disease remains unclear and it lacks any FDA-approved therapy. Interestingly, drug-induced Grover disease occurs in patients treated with B-RAF inhibitors that can paradoxically activate C-RAF and the downstream kinase MEK. We recently identified hyperactivation of MEK and ERK as key drivers of Darier disease, which is histologically identical to Grover disease, supporting our hypothesis that they share a pathogenic mechanism. To model drug-induced Grover disease, we treated human keratinocytes with clinically utilized B-RAF inhibitors dabrafenib or vemurafenib and leveraged a fluorescent biosensor to confirm they activated ERK, which disrupted intercellular junctions and compromised keratinocyte sheet integrity. Consistent with clinical data showing concomitant MEK blockade prevents Grover disease in patients receiving B-RAF inhibitors, we found that MEK inhibition suppressed excess ERK activity to rescue cohesion of B-RAF-inhibited keratinocytes. Validating these results, we demonstrated ERK hyperactivation in skin biopsies of vemurafenib-induced Grover disease, but also in spontaneous Grover disease. In sum, our data define a pathogenic role for ERK hyperactivation in Grover disease and support MEK inhibition as a therapeutic strategy.

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Section: Discussionmentioning

confidence: 77%

ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology

Simpson,

Tiwaa,

Zaver

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Exploring and clinical validation of prognostic significance and therapeutic implications of copper homeostasis-related gene dysregulation in acute myeloid leukemia

Abulimiti,

Jia,

et al. 2024

Ann Hematol

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Progress in the development of ERK1/2 inhibitors for treating cancer and other diseases

Grogan,

Shapiro

2024

Advances in Pharmacology

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MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives

Abstract: MEK1/2 are critical components of RAS–RAF–MEK–ERK or MAPK signalling pathway.

Cited by 5 publications

References 158 publications

ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology

ERK hyperactivation in epidermal keratinocytes impairs intercellular adhesion and drives Grover disease pathology

Exploring and clinical validation of prognostic significance and therapeutic implications of copper homeostasis-related gene dysregulation in acute myeloid leukemia

Progress in the development of ERK1/2 inhibitors for treating cancer and other diseases

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