School of Medicine and Health Sciences Poster Presentations

Title

The EGFR-Tyrosine Kinase Inhibitor, erlotinib, induces dermatitis that is enhanced by co-existing Mg-deficiency and attenuated by neurokinin-1 receptor blockade in a rodent model.

Document Type

Poster

Abstract Category

Cancer/Oncology

Keywords

Erlotinib, aprepitant, neurogenic inflammation, hypomagnesemia, side effects of EGFR-TKI anti-cancer therapy

Publication Date

Spring 5-1-2019

Abstract

Approximately 85% of patients treated with erlotinib (Tarceva) and other EGFR-TKIs develop skin rash consisting of papulo-pustular eruption, xerosis, pruritus, and hair/nail changes. Drug dose reductions (in 60% of patients) or discontinuation (32%) by oncologists have been reported, which may diminish therapeutic benefits. Using a Sprague-Dawley rat model, we found that prolonged treatment with erlotinib caused: moderate hypomagnesemia, elevated levels of the pro-inflammatory neuropeptide, substance P (SP), and enhanced systemic oxidative/nitrosative stress and that the SP (neurokinin-1 or NK-1) receptor blocker, aprepitant (Emend), significantly prevented erlotinib-mediated hypomagnesemia and attenuated oxidative/nitrosative stress. Aprepitant has been clinically used in short-term to prevent chemotherapy-induced nausea and vomiting in cancer patients, but benefits from longer use have not been considered. Nine week old rats were divided into 5 groups: Mg-sufficient (MgS, 100% RDA for Mg in diet, control), (MgS+erlotinib, MgS+erlotinib+aprepitant, Hypomagnesemic (MgD40, or 40% RDA) and (MgD40+erlotinib). Erlotinib (10 mg/kg/day) ± aprepitant (2 mg/kg/day) were administered with diet concurrently. Erlotinib caused significant decline in plasma Mg levels (14%, p<0.01) and significant rise in plasma SP levels (65%, p<0.01); plasma Mg declined 20% in MgD40 rats and 31 % in the MgD40 + erlotinib group, while SP levels were 27% and 85% higher, respectively, vs controls. Visual dermatological changes (+ to ++) were observed by 4-5 weeks in all erlotinib treated rats, which worsened (++ to +++) by weeks 8-11. Patchy alopecia on face and trunk, superficial skin reddening, pruritis, scabbing and/or crusting around nose, and rough coat were observed. Co-treatment with aprepitant diminished these adverse effects on the skin. Substantial upregulation of NK-1 receptors was observed in the epidermal cells and hair follicles of facial skin from 12 week erlotinib-treated rats; and aprepitant treatment attenuated this upregulation. Mg-restriction alone caused some elevation in epidermal cell and follicle NK-1 receptors, which was more pronounced in the MgD40 + erlotinib group. Treatment with aprepitant during prolonged erlotinib therapy (12 weeks) attenuated cutaneous side effects and hypomagnesemia Thus, the SPR (NK-1R) blocker, aprepitant, attenuated the cutaneous and other systemic side effects of EGFR-TKI therapy with erlotinib, and might indicate a novel clinical intervention against these side effects during anti-cancer therapy.

Open Access

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Presented at Research Days 2019.

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The EGFR-Tyrosine Kinase Inhibitor, erlotinib, induces dermatitis that is enhanced by co-existing Mg-deficiency and attenuated by neurokinin-1 receptor blockade in a rodent model.

Approximately 85% of patients treated with erlotinib (Tarceva) and other EGFR-TKIs develop skin rash consisting of papulo-pustular eruption, xerosis, pruritus, and hair/nail changes. Drug dose reductions (in 60% of patients) or discontinuation (32%) by oncologists have been reported, which may diminish therapeutic benefits. Using a Sprague-Dawley rat model, we found that prolonged treatment with erlotinib caused: moderate hypomagnesemia, elevated levels of the pro-inflammatory neuropeptide, substance P (SP), and enhanced systemic oxidative/nitrosative stress and that the SP (neurokinin-1 or NK-1) receptor blocker, aprepitant (Emend), significantly prevented erlotinib-mediated hypomagnesemia and attenuated oxidative/nitrosative stress. Aprepitant has been clinically used in short-term to prevent chemotherapy-induced nausea and vomiting in cancer patients, but benefits from longer use have not been considered. Nine week old rats were divided into 5 groups: Mg-sufficient (MgS, 100% RDA for Mg in diet, control), (MgS+erlotinib, MgS+erlotinib+aprepitant, Hypomagnesemic (MgD40, or 40% RDA) and (MgD40+erlotinib). Erlotinib (10 mg/kg/day) ± aprepitant (2 mg/kg/day) were administered with diet concurrently. Erlotinib caused significant decline in plasma Mg levels (14%, p<0.01) and significant rise in plasma SP levels (65%, p<0.01); plasma Mg declined 20% in MgD40 rats and 31 % in the MgD40 + erlotinib group, while SP levels were 27% and 85% higher, respectively, vs controls. Visual dermatological changes (+ to ++) were observed by 4-5 weeks in all erlotinib treated rats, which worsened (++ to +++) by weeks 8-11. Patchy alopecia on face and trunk, superficial skin reddening, pruritis, scabbing and/or crusting around nose, and rough coat were observed. Co-treatment with aprepitant diminished these adverse effects on the skin. Substantial upregulation of NK-1 receptors was observed in the epidermal cells and hair follicles of facial skin from 12 week erlotinib-treated rats; and aprepitant treatment attenuated this upregulation. Mg-restriction alone caused some elevation in epidermal cell and follicle NK-1 receptors, which was more pronounced in the MgD40 + erlotinib group. Treatment with aprepitant during prolonged erlotinib therapy (12 weeks) attenuated cutaneous side effects and hypomagnesemia Thus, the SPR (NK-1R) blocker, aprepitant, attenuated the cutaneous and other systemic side effects of EGFR-TKI therapy with erlotinib, and might indicate a novel clinical intervention against these side effects during anti-cancer therapy.