Arsenic circumvents the gefitinib resistance by binding to P62 and mediating autophagic degradation of EGFR in non-small cell lung cancer

Cell Death & Disease
Jianhua MaoSaijuan Chen

Abstract

Non-small cell lung cancer (NSCLC) is characterized by hyperexpression and/or gain-of-function mutations of the epidermal growth factor receptor (EGFR), resulting in an elevated overall kinase activity. Gefitinib is remarkably effective in patients with the L858R or ΔE746-A750-mutated of EGFR. However, drug resistance tends to develop because of the emergence of T790M mutation on EGFR. New strategies other than repressing kinase activity are thus required to treat NSCLC, thereby circumventing the resistance. In this study, arsenic trioxide (ATO) at 2 μM significantly inhibited the proliferation of the gefitinib-resistant NCI-H1975 cells of the EGFR L858R/T790M mutant compared with a modest inhibition in the gefitinib-sensitive HCC827 cells of ΔE746-A750 mutant and A549 cells of wild-type EGFR. Moreover, ATO significantly inhibited the overall kinase activity of EGFR primarily through quantitatively diminishing the EGFR in NCI-H1975 cells to an extent comparable with that reached by gefitinib in HCC827 cells. Furthermore, ATO promoted autophagic degradation of EGFR in NSCLC cells by directly binding to P62, which interacted with EGFR, preferentially the L858R/T790M mutant providing a plausible explanation for a more favorable ef...Continue Reading

References

May 16, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Masahiro FukuokaJosé Baselga
Jul 31, 2004·Science·Raffaella SordellaJeffrey Settleman
Feb 16, 2005·Cancer Cell·Jun ZhuHugues de Thé
Feb 25, 2005·The New England Journal of Medicine·Susumu KobayashiBalázs Halmos
Dec 27, 2005·Gene·Nicola NormannoDavid S Salomon
Feb 24, 2007·Nature Reviews. Cancer·Sreenath V SharmaDaniel A Haber
Jun 21, 2007·The Journal of Biological Chemistry·Serhiy PankivTerje Johansen
Jan 30, 2008·Proceedings of the National Academy of Sciences of the United States of America·Cai-Hong YunMichael J Eck
Apr 15, 2008·Nature Cell Biology·Valérie Lallemand-BreitenbachHugues de Thé
Sep 26, 2008·The New England Journal of Medicine·Roy S HerbstScott M Lippman
Feb 12, 2009·Proceedings of the National Academy of Sciences of the United States of America·Qun-Ye ZhangZhu Chen
Jun 16, 2009·Cell·Robin MathewEileen White
Aug 21, 2009·The New England Journal of Medicine·Tony S MokMasahiro Fukuoka
Dec 2, 2010·Proceedings of the National Academy of Sciences of the United States of America·Jian-Hua MaoSai-Juan Chen
Jan 12, 2011·Proceedings of the National Academy of Sciences of the United States of America·Hsin Hsien YehJuri G Gelovani
Feb 10, 2011·CA: a Cancer Journal for Clinicians·Suresh S RamalingamFadlo R Khuri
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
May 12, 2012·Nature Reviews. Cancer·Peter Kreuzaler, Christine J Watson
Sep 8, 2012·Cancer Biology & Therapy·Christopher FungUmamaheswar Duvvuri
Nov 19, 2015·Acta Pharmaceutica Sinica. B·Lihua Huang, Liwu Fu
Jan 9, 2016·CA: a Cancer Journal for Clinicians·Rebecca L SiegelAhmedin Jemal
Oct 23, 2016·Frontiers of Medicine·Shuhang WangDelong Liu

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Methods Mentioned

BETA
electron microscopy
co-IP
co-immunoprecipitation
pull-down
ubiquitination
transfection
surface plasmon resonance
xenograft
chip
xenografts

Software Mentioned

GraphPad Prism
Excel
Biacore T200 Evaluation
QuickChange® Primer Design
ImageQuant
Quantity One
Bioflux
LSM710 Pascal

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