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Remodeling of dermal adipose tissue alleviates cutaneous toxicity induced by anti-EGFR therapy
Leying Chen1, Qing You1, Min Liu1
1School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
Abstract:
Anti-epidermal growth factor receptor (EGFR) therapy-associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis, and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor γ (PPARγ) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPARγ by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPARγ represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy.
Insights
Activating peroxisome proliferator-activated receptor γ (PPARγ) with rosiglitazone can improve skin conditions caused by anti-epidermal growth factor receptor (EGFR) cancer therapy. This approach ameliorates rash severity without impacting antitumor effects.
Area of Science:
- Dermatology
- Oncology
- Adipose Tissue Biology
Background:
- Anti-epidermal growth factor receptor (EGFR) therapies can cause severe skin toxicity, impacting patient quality of life and treatment adherence.
- Currently, no effective clinical interventions exist to manage this adverse effect.
Purpose of the Study:
- To investigate the role of dermal white adipose tissue (dWAT) in EGFR inhibitor-induced skin rash.
- To identify therapeutic strategies for mitigating anti-EGFR therapy-associated cutaneous toxicity.
Main Methods:
- Utilized a murine model of EGFR inhibitor-induced rash.
- Assessed the impact of rosiglitazone, a PPARγ activator, on dWAT and skin conditions.
- Analyzed the molecular mechanisms involving PPARγ signaling, adipogenic differentiation, and IL6 expression.
Main Results:
- Atrophy of dWAT correlated with the occurrence and severity of rash in the murine model.
- Reduced dWAT resulted from inhibited adipogenic differentiation (via PPARγ defects) and increased lipolysis (via IL6 induction).
- Rosiglitazone treatment maintained adipogenic differentiation, repressed IL6, improved skin function, and ameliorated rash severity.
Conclusions:
- Activation of PPARγ is a promising therapeutic strategy for managing cutaneous toxicity associated with anti-EGFR therapy.
- This approach offers a way to improve skin health in cancer patients undergoing anti-EGFR treatment without compromising antitumor efficacy.
