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Van Der Steen et al. Cancer Drug Resist 2018;1:230-49 Cancer
DOI: 10.20517/cdr.2018.13 Drug Resistance

Review Open Access

Resistance to epidermal growth factor receptor
inhibition in non-small cell lung cancer

Nele Van Der Steen 1,2,3 , Elisa Giovannetti , Daniela Carbone , Alessandro Leonetti ,
1
1,4
5
Christian D. Rolfo , Godefridus J. Peters 1
6
1 Department of Medical Oncology, VU University Medical Center, Amsterdam 1081 HV, the Netherlands.
2 Department of Pathology, Antwerp University Hospital, Antwerp 2650, Belgium.
3 Center for Oncological Research, University of Antwerp, Antwerp 2610, Belgium.
4 Cancer Pharmacology Lab, AIRC Start-Up Unit, University of Pisa, Pisa 56124, Italy.
5 Medical Oncology Unit, University Hospital of Parma, Parma 43126, Italy.
6 University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, 21220 MD, USA.
Correspondence to: Dr. Elisa Giovannetti, Department of Medical Oncology, VU University Medical Center, Amsterdam 1081
HV, the Netherlands. E-mail: elisa.giovannetti@gmail.com
How to cite this article: Van Der Steen N, Giovannetti E, Carbone D, Leonetti A, Rolfo CD, Peters GJ. Resistance to epidermal
growth factor receptor inhibition in non-small cell lung cancer. Cancer Drug Resist 2018;1:230-49.
http://dx.doi.org/10.20517/cdr.2018.13

Received: 3 Aug 2018 First Decision: 28 Aug 2018 Revised: 5 Sep 2018 Accepted: 17 Sep 2018 Published: 19 Dec 2018
Science Editor: Jose Antonio Rodriguez Copy Editor: Yuan-Li Wang Production Editor: Zhong-Yu Guo

Abstract
Aberrant activation of the epidermal growth factor receptor (EGFR) is a driving force for cancer growth in a subgroup
of non-small cell lung cancer patients. These patients can be identified by the presence of activating EGFR mutations.
Currently three generations of EGFR-tyrosine kinase inhibitors (TKIs) have been approved by the Food and Drug
Administration and European Medicine Agency. This paper reviews the structure of EGFR and the downstream
signaling pathways of EGFR and describes the mechanisms of intrinsic and acquired resistance against EGFR-TKIs.
These mechanisms include secondary or tertiary mutations in EGFR, the activation of bypassing signaling pathways
or a histological transformation to small cell lung cancer. Moreover, drug efflux transporters will affect the cellular
accumulation of EGFR-TKIs and penetration of the first generation of EGFR-TKI into the brain. Lysosomal sequestration
of some EGFR-TKIs may also prevent the drugs to reach their target. In conclusion, resistance to EGFR-TKIs is
multifactorial, including primary and acquired mutations in the EGFR gene, activation of bypassing pathways and limited
uptake of drugs in the cells or target tissues. More pharmacological studies are needed in order to develop new specific
compounds targeted to overcome new resistance mechanisms in order to enable a personalized treatment approach.

Keywords: Epidermal growth factor receptor, non-small cell lung cancer, resistance, EGFR-tyrosine kinase inhibitors,
erlotinib, gefitinib, afatinib, osimertinib, rociletinib

© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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