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INTRODUCTION
Molecular characterization of non-small cell lung cancer (NSCLC) and subsequent identification of
targetable activated kinases led to a considerable shift in the treatment of this lethal disease in the past
two decades. In patients with oncogene addicted NSCLC, particularly in adenocarcinoma, standard
platinum-based chemotherapy has been replaced by molecularly driven strategies significantly improving
[1]
the outcomes for these patients . Among activated driver kinases suitable of pharmacological inhibition,
epidermal growth factor receptor (EGFR) represents the most investigated and targeted one. Under
physiological conditions, the EGFR signaling pathway controls cell growth, survival, proliferation, and
[2]
differentiation by conveying the signal from the cell surface to downstream targets . Oncogenic mutations
in EGFR usually increase the kinase activity of EGFR, thus leading to hyperactivation of the pro-survival
[3]
signaling pathway .
Approximately 50% of Asian patients and 11%-16% of patients from Western Countries with NSCLC
[4]
harbor mutations in EGFR . EGFR mutations are more often found in NSCLC from female never smokers,
[5,6]
and tumor histology is mainly adenocarcinoma . Three generations of specific EGFR-tyrosine kinase
inhibitors (TKIs) have been developed and partially implemented in clinical practice for the treatment of
EGFR-driven NSCLC up today: (1) gefitinib and erlotinib (first-generation); (2) afatinib and dacomitinib
[1]
(second-generation); and (3) osimertinib and rociletinib (third-generation) . Despite initial response and
tumor shrinkage, patients experience disease progression due to the onset of a resistance mechanism to
targeted treatment. This review will provide a comprehensive overview of current knowledge about EGFR
structure and EGFR mutations, focusing on resistance mechanisms to EGFR inhibition and additional
strategies to overcome treatment resistance.

Structure and activation of wild-type EGFR
EGFR is a transmembrane receptor protein that belongs to the ErbB family of tyrosine kinases. EGFR is
made up of an extracellular domain, also known as ligand binding region, a transmembrane region and an
[7]
intracellular tyrosine kinase domain . The EGFR kinase domain consists of two lobes: a C-terminal lobe
(C-lobe) and an N-terminal lobe (N-lobe). The catalytic site is located in the cleft between these two lobes.
As illustrated in Figure 1, the catalytic site contains the activation loop (A-loop) (contributed by the
C-lobe), the regulatory C-helix and the nucleotide phosphate binding loop (P-loop) (both contributed by
[8]
the N-lobe) .
For the activation of a tyrosine kinase receptor, two important conditions must be met. Firstly, the critical
amino acids need to be positioned correctly to allow transfer of the phosphate group. Secondly, the peptide
substrate binding site needs to be accessible . In EGFR, the A-loop occludes the peptide substrate binding
[9]
site. The C-loop contains a catalytic important glutamate that, together with Lys, is necessary for the
coordination of the α- and β-phosphate groups on ATP . The P-loop also contributes to the coordination
[10]
[3]
of ATP through its GXGXXG motif .
In wild-type EGFR, the binding of EGF causes dimerization of the EGFR-receptor in a head-to-tail
manner . Hereby, the C-lobe of the one receptor pushes the N-lobe of the second receptor away, which
[11]
leads to a reorientation of the A-loop. This leads to a translocation of the regulatory C-lobe to its active
position , whereby Glu can interact with Lys. Furthermore, the peptide substrate binding site becomes
[11]
[10]
accessible .
EGFR signaling
After binding to its ligand, EGFR frequently heterodimerizes with its family members Her2, Her3 and
[12]
[13]
Her4 . Eleven ligands are known within the family, of which EGF binds EGFR with the highest affinity .
Signaling through EGFR can be divided in two main categories: kinase-dependent and kinase-independen