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Almeida et al. J Cancer Metastasis Treat 2021;7:57 https://dx.doi.org/10.20517/2394-4722.2021.108 Page 5 of 10

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cells to the CD8 T stimuli suggests that LSPCs in favorable-risk AML cases display a higher dependence on
the microenvironment to expand [Figure 1]. We found that EGF bone marrow plasma levels were lower in
APL patients when compared to healthy control subjects. In addition, AREG was detected in 5/17 APL bone
marrow plasma samples and absent in 20 control samples. However, the significance of these ligands in APL
development remains to be determined once our in vivo data show that gefitinib treatment did not provide
additional survival benefit in a transgenic mouse model of APL. (de Almeida LY and Rego EM, own
unpublished observation, 15 June 2021).

EGFR ligands exert distinct functions depending on the biological context and on what type of cell they
originate. Ramadan et al. experimentally demonstrated that a specific T cell subtype [T9 IL-33 (interleukin-9-
[45]
producing T cells activated via the ST2-IL-33 pathway)], responsible for graft-vs.-leukemia reactivity,
express high levels of AREG, and the AREG blockade on T cells increased graft-vs.-host disease severity in
vivo, but it did not affect their ability to kill myeloid leukemia cells in vitro. In chronic myeloid leukemia
(CML), CML cell-derived exosomes carrying AREG activated the EGFR signaling in stromal cells, which in
turn secreted IL-8, stimulating the proliferation of leukemic cells . Furthermore, in the context of
[46]
myelosuppression, EGF promoted survival and regeneration of hematopoietic stem cells following
irradiation , thereby providing a beneficial improvement for myeloid reconstitution. Together, these
[47]
findings suggest that EGFR ligands have important pathological and protective functions in myeloid
leukemogenesis.

THE ROLE OF EGFR TKI IN THE TREATMENT OF AML
Since EGFR activation is involved in cancer progression, a variety of drugs targeting this signaling pathway
have been developed and proven to be effective in the treatment of solid tumors and, particularly, in
NSCLC . The main classes of FDA-approved drugs that act on the EGFR pathway are monoclonal
[48]
antibodies (e.g., cetuximab and panitumumab), which bind to the EGFR extracellular domain competing
with endogenous ligands, and the TKI (e.g., gefitinib, erlotinib, and afatinib), which block the intracellular
domain of this receptor, impairing the activation of cell signaling cascades that promote the proliferation of
malignant cells [49-51] . EGFR-based therapies were also tested in leukemic settings, demonstrating to induce
apoptosis and differentiation of AML cell lines and primary blasts at low micromolar concentrations that
+
are achievable in clinical practice, as summarized in Table 1. Noteworthy, unlike healthy CD34 cells,
erlotinib particularly induced AML-derived CD34 cells apoptosis in a time- and dose-dependent
+
[2]
manner . In addition, a complete remission of AML in two adult patients with concurrent NSCLC was
obtained after treatment with erlotinib [35,52] . Although EGFR gene expression may be clinically useful for
predicting AML outcomes [5,33,34] , the receptor was not detected in the blasts of these patients, suggesting that
erlotinib probably acted via EGFR-independent mechanisms. Thus, based on the controversial data
regarding EGFR expression in AML samples, further studies analyzed the cross-pharmacological
interactions of EGFR TKI to predict potential off-targets. In this regard, preclinical data demonstrate that
erlotinib induces apoptosis in AML cells by inhibiting JAK-2 and STAT-5 and reduced the activation of
[2]
SFK and mTOR signaling pathways , which are constitutively activated in AML blasts. In addition,
[17]
[15]
proteomic and genetic approaches identified SYK as a gefitinib target for AML differentiation in vitro . It
is particularly noteworthy that increased expression of phosphorylated SYK in AML samples, especially in
those harboring internal tandem duplication mutations in the FLT3 gene (FLT3-ITD), was related to
unfavorable clinical outcomes [53,54] . Recently, Cao et al. demonstrated that erlotinib plays a dual role
[16]
targeting FLT3 in FLT3-ITD mutant AML cells and SYK and Lyn, another TK associated with leukemia
proliferation, in FLT3-ITD negative AML cells, thereby showing a potential advantage of erlotinib use to
overcome the cellular heterogeneity that exists in AML.