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INTRODUCTION
Epidermal growth factor receptor (EGFR) is a type of tyrosine kinase (TK) receptor recognized as an
important player in the tumor biology of many solid neoplasms, making it a key target for therapeutic
strategies, especially in non-small cell lung cancer (NSCLC). EGFR TK inhibitors (TKI) have demonstrable
efficacy in the treatment of patients with EGFR-mutated NSCLC with a favorable impact on progression-
[1,2]
free survival, but not in the subgroup of EGFR wild-type tumors . In contrast, EGFR mutations are rarely
[3,4]
found in AML , while their expression has been reported to be associated with poor prognostic
outcomes . Accordingly, in vitro, ex vivo, and in vivo results demonstrate that EGFR TKI induces terminal
[5]
differentiation and cell death of AML cells [2,6-8] . Moreover, in the bone marrow microenvironment,
interactions between leukemia stem/progenitor cells (LSPCs) and immune cells promoted the expansion of
leukemia cell subsets, which was associated with the upregulation of interleukin (IL)-3 gene expression in
[11]
LSPCs [Figure 1] [9,10] . Of note, Radpour et al. showed that, in favorable-risk AML, IL-3 gene expression in
CD34 LSPCs was positively correlated with EGF/EGFR gene expression in CD8 T cells. Furthermore, this
+
+
finding was functionally validated in a co-culture system with CD8 T cells and CD34 LSPC. Accordingly,
+
+
+
CD8 T cells promoted the expansion of LSPC by increasing IL-3 mRNA and protein. On the other hand,
IL-3 gene expression and cell proliferation were reduced in LSPC in the presence of the neutralizing
antibody to EGFR . Together, these data support the idea that EGFR TKI could be a promising alternative
[11]
therapy to treat AML. However, EGFR expression is low or absent in most AML samples and cell lines [2,5,12] ,
indicating that the anti-proliferative and pro-apoptotic effects of EGFR TKI may occur by EGFR-
independent mechanisms, through interaction with other TK receptors [2,6,7,13,14] . Among them, preclinical
[15]
[16]
data identify SYK (Spleen tyrosine kinase) , Lyn , other TK of the Src family kinases (SFKs) , signal
[17]
transducer and activator of transcription 5, and Janus kinase 2 as off-targets of the EGFR TKI erlotinib
[2]
and gefitinib in AML cells. However, it needs to be pointed out that no difference in survival or objective
response was observed in clinical trials of patients with AML in which EGFR TKI was administered [18-20] .
Therapeutic strategies that target the EGFR pathway have received considerable attention in other oncologic
settings, but it is still unclear which patients with AML may benefit from EGFR TKI therapy. In this review,
we summarize the knowledge regarding the role of the EGFR signaling pathway in AML and provide an
overview of experimental and clinical studies using EGFR TKI to suppress leukemia progression.

EGFR
EGFR (also described as HER1 and ERBB1) is a transmembrane glycoprotein (170 kDa) that belongs to the
HER family of TK receptors, which comprises four members (HER1 or EGFR, HER2, HER3, and HER4)
and plays an important role in regulating cell proliferation, survival, differentiation, angiogenesis, and
metastatic spread [21-23] . The extracellular domain of this receptor can bind to seven official different types of
ligands: EGF, transforming growth factor-alpha, amphiregulin (AREG), EGF-like heparin-binding factor
(HB-EGF), betacellulin, epiregulin (EPR), and epigen [24,25] . Moreover, the connective tissue growth factor
(CTGF/CCN2) has been identified as a new EGFR ligand . Interestingly, the affinity of EGFR can be
[26]
varied, depending on the specific ligand, tissue, and physiological and pathological conditions, which cause
different cellular responses [27-29] . The interactions of EGFR with its ligands induce the homodimerization or
heterodimerization of the receptor with another member of the HER family. Dimerization leads to EGFR
autophosphorylation at specific tyrosine residues in the intracellular domain, triggering the activation of
downstream signaling pathways, such as mitogen-activated protein kinases (MAPK), phosphatidylinositol
3-kinase/protein kinase B (PI3K/AKT), and Janus-activated kinase/signal transducer and activator of
transcription (JAK-STAT) [24,25] .