ArticleThe Journal of clinical investigation2020
IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 57 citations in OpenAlex.
- Jiedu Xiaozhen Granules for Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor-Mediated Skin Toxicity: Protocol for a Randomized Controlled Trial.JMIR research protocols · 2026Article
- Acneiform drug eruptions-update on pathophysiology and culprit drugs.Frontiers in medicine · 2026Review
- Papulopustular eruptions associated with EGFR-pathway-related targeted therapies: clinical spectrum, evidence boundaries, folliculocentric inflammation, and management considerations.Frontiers in oncology · 2026Review
- Managing skin-related adverse events during mirdametinib treatment for NF1-PNs: expert guidance from the ReNeu trial.Frontiers in oncology · 2026Review
- Chinese botanical drugs for mitigating epidermal growth factor receptor-targeted therapy-associated cutaneous toxicity: immune mechanisms and translational pathways.Frontiers in pharmacology · 2026Review
- Drug-induced cutaneous toxicities in solid tumor oncology: mechanisms, manifestations, and management.Medical oncology (Northwood, London, England) · 2025Review
- Skin Reactions and Other Underappreciated Dermatologic Side Effects of Cancer Therapies.Current treatment options in oncology · 2025Review
- Brigatinib can inhibit proliferation and induce apoptosis of human immortalized keratinocyte cells.Frontiers in pharmacology · 2025Article
- JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia.EMBO molecular medicine · 2024Article
- PPP3CB overexpression mediates EGFR TKI resistance in lung tumors via calcineurin/MEK/ERK signaling.Life science alliance · 2024Article
- CD2 expressing innate lymphoid and T cells are critical effectors of immunopathogenesis in hidradenitis suppurativa.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Cancer Therapy-induced Dermatotoxicity as a Window to Understanding Skin Immunity.Hematology/oncology clinics of North America · 2024Review
- Inflammatory loop involvingHeliyon · 2024Article
- The use of epidermal growth factor in dermatological practice.International wound journal · 2023Review
- Targeting IL-36 in Inflammatory Skin Diseases.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2023Article
- The Riddle of Cetuximab-Related Skin Toxicity:Cancers · 2022Article
- Treponema denticola Induces Interleukin-36γ Expression in Human Oral Gingival Keratinocytes via the Parallel Activation of NF-κB and Mitogen-Activated Protein Kinase Pathways.Infection and immunity · 2022Article
- Non-immune and immune functions of interleukin-36γ suppress epithelial repair at the ocular surface.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2022Article
- Remodeling of dermal adipose tissue alleviates cutaneous toxicity induced by anti-EGFR therapy.eLife · 2022Article
- Co-Treatment of Chloroquine and Trametinib Inhibits Melanoma Cell Proliferation and Decreases Immune Cell Infiltration.Frontiers in oncology · 2022Article
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/MEKi) are beneficial for the treatment of solid cancers but are frequently associated with severe therapy-limiting acneiform skin toxicities. The underlying molecular mechanisms are poorly understood. Using gene expression profiling we identified IL-36γ and IL-8 as candidate drivers of EGFRi/MEKi skin toxicity. We provide molecular and translational evidence that EGFRi/MEKi in concert with the skin commensal bacterium Cutibacterium acnes act synergistically to induce IL-36γ in keratinocytes and subsequently IL-8, leading to cutaneous neutrophilia. IL-36γ expression was the combined result of C. acnes-induced NF-κB activation and EGFRi/MEKi-mediated expression of the transcription factor Krüppel-like factor 4 (KLF4), due to the presence of both NF-κB and KLF4 binding sites in the human IL-36γ gene promoter. EGFRi/MEKi increased KLF4 expression by blockade of the EGFR/MEK/ERK pathway. These results provide an insight into understanding the pathological mechanism of the acneiform skin toxicities induced by EGFRi/MEKi and identify IL-36γ and the transcription factor KLF4 as potential therapeutic targets.
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