Minocycline Prevents and Repairs the Skin Disorder Associated with Afatinib, One of the Epidermal Growth Factor Receptor-tyrosine Kinase Inhibitors for Non-small Cell Lung Cancer

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2020 Apr 8

PMID 32252690

Citations 9

Authors

Kazumi Sano

Kazuhiko Nakadate

Kazuhiko Hanada

Affiliations

Soon will be listed here.

Abstract

Background: While epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) exert a breakthrough effect, the incidence of skin disorders as a side effect has significantly reduced patients' quality of life. This study aimed to develop a treatment for inflammatory ulcers as one of the side effects of afatinib (Giotrif®), a second-generation EGFR-TKI, and established a skin disorder mouse model to investigate the protective effect of minocycline.

Methods: First, under inhalation anesthesia with isoflurane, the back of a male ddy mouse was shaved, and afatinib petrolatum was applied alone or in combination with minocycline to observe the state of the skin and measure transepidermal water transpiration (TEWL). Next, afatinib was administered orally to mice, and minocycline petrolatum was applied to observe whether the skin disorder was prevented and its effect on repair of the skin disorder.

Results: Skin injury occurred on the back of the mouse following afatinib (1 mg/g in petrolatum) application, and scab formation was observed. Application of minocycline prevented and improved the skin disorder caused by afatinib. When the minocycline-petrolatum mixture was applied to the mouse that developed the skin disorder, a significant improvement in TEWL was observed, and skin repair was observed macroscopically.

Conclusions: These results suggest that minocycline petrolatum applied locally prevents and repairs afatinib-induced skin disorders of non-small cell lung cancer patients. Histological examination of skin has provided insights into the mechanism of the occurrence of afatinib-related skin disorder and suggested the efficacy of minocycline topical application in clinical practice.

Citing Articles

Skin microbial dysbiosis is a characteristic of systemic drug-related intertriginous and flexural exanthema-like lesions induced by EGFR inhibitor.

Liu W, Peng L, Chen L, Wan J, Lou S, Yang T Heliyon. 2023; 9(11):e21690.

PMID: 38028014 PMC: 10661433. DOI: 10.1016/j.heliyon.2023.e21690.

Drug Repurposing in Non-Small Cell Lung Carcinoma: Old Solutions for New Problems.

Doumat G, Daher D, Zerdan M, Nasra N, Bahmad H, Recine M Curr Oncol. 2023; 30(1):704-719.

PMID: 36661704 PMC: 9858415. DOI: 10.3390/curroncol30010055.

Home-based multidisciplinary interventions on skin adverse reactions in EGFR-TKI-treated patients with lung cancer: a protocol for a randomised controlled trial.

Du R, Yang H, Zhou H, Ma L, Getu M, Chen C BMJ Open. 2022; 12(11):e063921.

PMID: 36442902 PMC: 9710339. DOI: 10.1136/bmjopen-2022-063921.

Du R, Wang X, Zhou H, Ma L, Larcher L, Chen C Support Care Cancer. 2022; 30(12):9889-9899.

PMID: 36400979 DOI: 10.1007/s00520-022-07451-2.

Experience of patients with lung cancer and with targeted therapy-related skin adverse drug reactions: A qualitative study.

Du R, Yang H, Zhu J, Zhou H, Ma L, Getu M Asia Pac J Oncol Nurs. 2022; 9(10):100115.

PMID: 36118625 PMC: 9479359. DOI: 10.1016/j.apjon.2022.100115.

References

Shinohara A, Ikeda M, Okuyama H, Kobayashi M, Funazaki H, Mitsunaga S . Efficacy of prophylactic minocycline treatment for skin toxicities induced by erlotinib plus gemcitabine in patients with advanced pancreatic cancer: a retrospective study. Am J Clin Dermatol. 2015; 16(3):221-9. DOI: 10.1007/s40257-015-0116-x. View

Hashimoto N, Nakamichi N, Yamazaki E, Oikawa M, Masuo Y, Schinkel A . P-Glycoprotein in skin contributes to transdermal absorption of topical corticosteroids. Int J Pharm. 2017; 521(1-2):365-373. DOI: 10.1016/j.ijpharm.2017.02.064. View

Metz L, Li D, Traboulsee A, Duquette P, Eliasziw M, Cerchiaro G . Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. N Engl J Med. 2017; 376(22):2122-2133. DOI: 10.1056/NEJMoa1608889. View

Lichtenberger B, Gerber P, Holcmann M, Buhren B, Amberg N, Smolle V . Epidermal EGFR controls cutaneous host defense and prevents inflammation. Sci Transl Med. 2013; 5(199):199ra111. DOI: 10.1126/scitranslmed.3005886. View

Hashimoto N, Nakamichi N, Uwafuji S, Yoshida K, Sugiura T, Tsuji A . ATP binding cassette transporters in two distinct compartments of the skin contribute to transdermal absorption of a typical substrate. J Control Release. 2012; 165(1):54-61. DOI: 10.1016/j.jconrel.2012.10.011. View

Kadi A, Abdelhameed A, Darwish H, Attwa M, Al-Shakliah N . A highly efficient and sensitive LC-MS/MS method for the determination of afatinib in human plasma: application to a metabolic stability study. Biomed Chromatogr. 2015; 30(8):1248-55. DOI: 10.1002/bmc.3674. View

Wind S, Schnell D, Ebner T, Freiwald M, Stopfer P . Clinical Pharmacokinetics and Pharmacodynamics of Afatinib. Clin Pharmacokinet. 2016; 56(3):235-250. PMC: 5315738. DOI: 10.1007/s40262-016-0440-1. View

Arrieta O, Vega-Gonzalez M, Lopez-Macias D, Martinez-Hernandez J, Bacon-Fonseca L, Macedo-Perez E . Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients. Lung Cancer. 2015; 88(3):282-8. DOI: 10.1016/j.lungcan.2015.03.019. View

Dixit A, Srivastava G, Verma D, Mishra M, Singh P, Prakash O . Minocycline, levodopa and MnTMPyP induced changes in the mitochondrial proteome profile of MPTP and maneb and paraquat mice models of Parkinson's disease. Biochim Biophys Acta. 2013; 1832(8):1227-40. DOI: 10.1016/j.bbadis.2013.03.019. View

10.

Sparidans R, Rosing H, Rood J, Schellens J, Beijnen J . Liquid chromatography-tandem mass spectrometric assay for therapeutic drug monitoring of the B-Raf inhibitor encorafenib, the EGFR inhibitors afatinib, erlotinib and gefitinib and the O-desmethyl metabolites of erlotinib and gefitinib in human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. 2016; 1033-1034:390-398. DOI: 10.1016/j.jchromb.2016.09.012. View

11.

Melosky B, Anderson H, Burkes R, Chu Q, Hao D, Ho V . Pan Canadian Rash Trial: A Randomized Phase III Trial Evaluating the Impact of a Prophylactic Skin Treatment Regimen on Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor-Induced Skin Toxicities in Patients With Metastatic Lung Cancer. J Clin Oncol. 2015; 34(8):810-5. DOI: 10.1200/JCO.2015.62.3918. View

12.

Goto A, Ozawa Y, Koda K, Akahori D, Koyauchi T, Amano Y . Clinical impact of minocycline on afatinib-related rash in patients with non-small cell lung cancer harboring epidermal growth factor receptor mutations. Respir Investig. 2018; 56(2):179-183. DOI: 10.1016/j.resinv.2017.11.009. View

13.

Nakadate K, Motojima K, Hirakawa T, Tanaka-Nakadate S . Progressive Depletion of Rough Endoplasmic Reticulum in Epithelial Cells of the Small Intestine in Monosodium Glutamate Mice Model of Obesity. Biomed Res Int. 2016; 2016:5251738. PMC: 4942597. DOI: 10.1155/2016/5251738. View

14.

Perez-Soler R, Saltz L . Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining?. J Clin Oncol. 2005; 23(22):5235-46. DOI: 10.1200/JCO.2005.00.6916. View

15.

Torigoe K, Tominaga M, Ko K, Takahashi N, Matsuda H, Hayashi R . Intrathecal Minocycline Suppresses Itch-Related Behavior and Improves Dermatitis in a Mouse Model of Atopic Dermatitis. J Invest Dermatol. 2016; 136(4):879-881. DOI: 10.1016/j.jid.2015.12.037. View

16.

Garrido-Mesa N, Zarzuelo A, Galvez J . Minocycline: far beyond an antibiotic. Br J Pharmacol. 2013; 169(2):337-52. PMC: 3651660. DOI: 10.1111/bph.12139. View

17.

Moller T, Bard F, Bhattacharya A, Biber K, Campbell B, Dale E . Critical data-based re-evaluation of minocycline as a putative specific microglia inhibitor. Glia. 2016; 64(10):1788-94. DOI: 10.1002/glia.23007. View

18.

Ashida A, Ogawa E, Uhara H, Koizumi T, Okuyama R . Inhibition of epidermal growth factor receptor induces tumor necrosis factor-α via activation of peroxisome proliferator-activated receptor-γ and nuclear factor-κB in sebocytes: A possible pathogenesis of papulopustular rash. J Dermatol Sci. 2016; 82(1):53-6. DOI: 10.1016/j.jdermsci.2015.12.004. View

19.

Surguladze D, Deevi D, Claros N, Corcoran E, Wang S, Plym M . Tumor necrosis factor-alpha and interleukin-1 antagonists alleviate inflammatory skin changes associated with epidermal growth factor receptor antibody therapy in mice. Cancer Res. 2009; 69(14):5643-7. DOI: 10.1158/0008-5472.CAN-09-0487. View