Heredity and aging are common risk factors for cancer and Alzheimer’s disease (AD), which are the leading causes of death worldwide (White et al., 2014; Guerreiro and Bras, 2015; Majd et al., 2019). Numerous anti-cancer therapies are available, but therapeutic drugs for AD are scarce. AD is the most common neurodegenerative disease characterized by amyloid and tau protein aggregation and cognitive decline (Ates et al., 2016). Amyloid and tau protein aggregates are not only pathophysiological biomarkers of AD, but also cause neuronal loss, synapse destruction, and neuroinflammation (Serrano-Pozo et al., 2011; Krstic and Knuesel, 2013). Other potential mechanisms of AD progression are oxidative stress and epigenetic dysfunction.

Several studies have found an inverse association between cancer and AD, but others have argued for a parallel relationship (Majd et al., 2019; Nudelman et al., 2019; Branigan et al., 2021; Zhang et al., 2022). Although the underlying mechanism of the relationship between cancer and AD has not been thoroughly investigated, the diseases share hallmarks and risk factors. Risk factors for both cancer and AD include aging, smoking, obesity, and type 2 diabetes (Cannata et al., 2010; Cataldo et al., 2010; Mayeux and Stern, 2012; White et al., 2014; Emmerzaal et al., 2015). Strikingly, cell-cycle entry, which is required for cancer pathogenesis, is high in patients with AD (Majd et al., 2019). At the cellular level, the pathogenesis of AD and cancer both involve the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway, which regulates cell proliferation, metabolism, growth, and autophagy (Pei and Hugon, 2008; Morgan et al., 2009; Advani, 2010; Talbot et al., 2012; Fumarola et al., 2014; Porta et al., 2014). Abnormal growth suppressor evasion is also observed in both cancer and AD. Specifically, cell growth and division in cancer often occur through inactivating mutations of tumor suppressors such as retinoblastoma transcriptional corepressor 1 (RB1) and TP53 (Hanahan and Weinberg, 2011; Fischer et al., 2016; Robinson et al., 2017). In patients with AD, levels of p27, a critical negative cell cycle regulator, are significantly reduced (Ogawa et al., 2003; Munoz et al., 2008). The systemic dysregulation of the cell cycle in both cancer and AD supports a correlation between these two diseases. Angiogenesis, cell adhesion inhibition, and inflammation are also shared by cancer and AD (Nudelman et al., 2019). Therefore, verifying the commonalities between cancer and AD might contribute to the development of effective therapeutic strategies.

A genome-wide association study found a significant positive genetic correlation between cancer and AD, implying that the pathophysiology of cancer and AD share common genetic variants (Feng et al., 2017). Specifically, super-enhancer, a broad enhancer domain affecting cell type identification and function, exhibits a significant positive genetic correlation with cancer and AD, indicating a potential role of gene expression regulation in the common genetic etiologies of cancer and AD (Feng et al., 2017; Zhao et al., 2022). Several genes [e.g., epidermal growth factor receptor (EGFR) and amyloid precursor protein (APP)] are associated with both cancer and AD, and we and others have recently found that anti-cancer drugs can penetrate the blood-brain barrier (BBB) and modulate AD pathology (Ryu and McLarnon, 2008; Cramer et al., 2012). Specifically, inhibitors of EGFR and other tyrosine kinases, which are multitarget enzymes, may have practical value for treating cancer and AD (Mansour et al., 2021c). This review provides insights into the potential roles of EGFR and EGFR inhibitors in cancer and AD and related therapeutic strategies.

EGFR is a cell surface growth factor receptor that regulates cell proliferation, differentiation, and survival (Yewale et al., 2013). EGFR was the first receptor tyrosine kinase (RTK) to be discovered and is a member of the ErbB family of RTKs (Wong and Guillaud, 2004; Roskoski, 2019). The EGFR gene contains 31 exons and encodes a 170-kDa transmembrane glycoprotein (Mitsudomi and Yatabe, 2010; Sabbah et al., 2020). EGFR is stimulated by ligands such as epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α) (Purba et al., 2017). Upon binding to the extracellular domain of EGFR, these ligands induce conformational changes in the receptor that facilitate the formation of receptor dimers or oligomers (Schlessinger, 2002). EGFR dimerization triggers the activation of its intrinsic tyrosine kinase activity and subsequent autophosphorylation of several tyrosine residues in the EGFR C-terminal domain (Yu et al., 2002). These phosphorylated tyrosine residues serve as docking sites for various signaling molecules and initiate canonical EGFR signaling pathways (Lemmon and Schlessinger, 2010). Although numerous reviews have discussed EGFR as a target in cancer, inflammatory diseases, and monogenic diseases, the regulation of EGFR expression or signaling as a multi-disease target requires further investigation.

EGFR plays an essential physiological role in regulating the development of epithelial tissue and homeostasis and hence is also linked to tumorigenesis, including lung cancer, breast cancer, and glioblastoma (Sigismund et al., 2018). EGFR is a critical modulator and a target for developing novel therapeutic strategies in various cancers. EGFR signaling modulates cancer cell proliferation through several metabolic processes (Sigismund et al., 2018). For example, Srivatsa et al. (2017) found that EGFR-expressing myeloid cells are abundant in the colorectal tumor stroma, indicating that EGFR in tumor-associated myeloid cells may be a diagnostic biomarker for colorectal cancer (CRC). CRISPR/Cas9-mediated elimination of EGFR significantly inhibits tumor cell growth and activates the mitogen-activated protein kinase (MAPK) (p-ERK1/2) pathway (Liu et al., 2020). Moreover, Song et al. (2020) identified upregulation of EGFR and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in breast cancer tissues.

The EGFR pathway is a widely recognized oncogenic pathway for non-small cell lung cancer (NSCLC), which represents approximately 75% of lung cancers (Bethune et al., 2010; Hsu et al., 2019). The EGFR pathway regulates the Bax/B-cell lymphoma 2 (Bcl-2) cascade, which is associated with apoptosis in NSCLC (Alam et al., 2022). Interestingly, a study identified EGFR overexpression or mutations in intracellular EGFR in 43%–89% of NSCLC cases (Gupta et al., 2009). Exon 19 deletion and L858R point mutation are the most frequent EGFR mutations in NSCLC (Khaddour et al., 2021). Activating somatic mutations in exons 18–21 of EGFR in NSCLC can continuously activate the EGFR kinase domain regardless of ligand binding and result in sustained downstream signaling. Several studies have reported that EGFR expression is increased by 40%–89% in NSCLC (Lu et al., 2001; Lynch et al., 2004; Al Olayan et al., 2012). Shao et al. (2022) found that upregulated EGFR signaling induces increased levels of the membrane-bound complement regulatory proteins (mCRPs) CD55 and CD59, thereby promoting tumor immune evasion in lung cancer cells (CD8⁺T). In addition, Ohsaki et al. (2000) observed shorter survival of NSCLC patients with EGFR overexpression. Selvaggi et al. (2004) found that EGFR expression is significantly increased in stage III of NSCLC, implying that EGFR levels are a potential prognostic factor. Merrick et al. (2006) observed a significantly positive relationship between EGFR expression and the progression of bronchial dysplasia, a precursor of lung carcinoma, indicating a role of EGFR upregulation in lung cancer development and progression. Yang et al. (2015) reported that EGFR mutation-mediated lung cancer is associated with downregulation of cluster of differentiation 82 (CD82), which promotes EGFR expression. Shien et al. (2012) discovered that EGFR silencing by siRNA significantly reduces the cell viability of EGFR-mutant cell lines (PC-9, HCC827, NCI-H820, and NCI-1975), further supporting EGFR as a promising therapeutic target in NSCLC. This critical role of EGFR upregulation in the development, progression, and longevity of lung cancer has led to the development of drugs that control EGFR activity and expression.

The general functions of EGFR in the central nervous system (CNS) include neural stem cell pool maintenance, astrocyte differentiation and maturation, oligodendrocyte maturation, and neurite outgrowth (Romano and Bucci, 2020). EGFR isoforms are expressed in neurons in the hippocampus, cerebellum, and cerebral cortex (Wong and Guillaud, 2004). Several recent studies have demonstrated that EGFR and its related signaling pathways that it mediates are crucial targets for modulating AD pathology. For instance, Wang et al. (2013) found that EGFR activation (p-EGFR/EGFR) is significantly increased in 8-month-old APP/PS1 mice (a model of AD) compared with wild-type mice. Excessive EGFR expression induces memory impairment in Aβ-overexpressing Drosophila (Prüßing et al., 2013). More importantly, dual overexpression of EGFR and Aβ₄₂ synergistically promotes memory loss, implying that EGFR is upregulated in AD (Chiang et al., 2010). Notably, EGFR upregulation was recently shown to induce Aβ₄₂ neurotoxicity and neuroinflammation and activate astrocytes (Ozbeyli et al., 2017; Chen et al., 2019b). AD patients exhibit neuritic plaques with EGFR expression in the cerebral cortex and hippocampus (Birecree et al., 1988). However, EGF treatment does not alter EGFR or Aβ levels in the brain and prevents cognitive dysfunction in E4FAD mice (Thomas et al., 2016). Taken together, the literature suggests that inhibition of EGFR modulates Aβ plaque accumulation, neuroinflammation, and cognitive function in mouse models of AD. Although there are conflicting reports regarding the role of EGFR in Aβ pathology, there is strong evidence that EGFR is a dual molecular target for cancer and AD (Figure 1A).

Despite substantial investments of resources and time in identifying new drugs for AD, clinical trials have produced disappointing results. Thus, the effects of EGFR on Aβ, neuroinflammation, and cognitive function have spurred growing interest in the potential repurposing of EGFR inhibitors used as anti-cancer drugs for the treatment of AD (Mansour et al., 2021c). The molecular mechanisms of EGFR in cancer and AD are also being investigated to develop disease-modifying drugs. Chen et al. (2019b) found that oxygen-glucose deprivation (OGD) increases EGFR phosphorylation and triggers downstream protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling pathways in primary cultured astrocytes and CTX-TNA2 cells. Characterization of EGFR signaling pathways and downstream cascades may reveal promising strategies for utilizing tyrosine kinase inhibitors (TKIs) as disease-modifying therapies in cancer and AD. In addition, EGFR TKIs have greater BBB penetration potential than most intravenous chemotherapies (Ahluwalia et al., 2018). A recent high-performance liquid chromatography (HPLC) analysis showed that ibrutinib can cross the BBB in WT mice (Lee et al., 2021a), and gefitinib, erlotinib, afatinib, varlitinib, lapatinib, and osimertinib are all known to cross the BBB (Lin et al., 2008; Babu et al., 2015; Mansour et al., 2021b; Colclough et al., 2021). Colclough et al. (2021) compared the BBB permeability of EGFR TKIs and found that osimertinib has the highest BBB penetration, with a Kpuu of 0.21, followed by Kpuu values of 0.084 for erlotinib, 0.0092 for gefitinib, and 0.0046 for afatinib. The low BBB permeability of erlotinib and gefitinib means that these drugs do not exhibit significant or persistent effects in the brain (Ahluwalia et al., 2018). Although the abilities of lapatinib, osimertinib, and CL-387,785 to penetrate the BBB have not been determined, lapatinib is expected to cross the BBB due to its low molecular weight and lipophilicity (Mansour et al., 2021b). However, studies of the use of BBB-penetrating EGFR inhibitors to treat AD remain scarce, and the mechanisms of BBB-permeable EGFR TKIs in AD remain to be elucidated. Several anti-cancer EGFR inhibitors that are candidates for AD therapy are described below, and the therapeutic effects, safety, and toxicity profiles of EGFR TKIs in cancer and AD are shown in Tables 1, 2; Figure 1B.

Several recent studies have revealed associations of EGFR with cancer and AD; thus, regulating EGFR expression may be a strategy for treating both diseases. However, comprehensive studies of the roles of EGFR and EGFR inhibitors (TKIs) in cancer and AD are not available. In addition, although EGFR is a potential target for AD treatment, the effectiveness of major anti-cancer EGFR TKIs as AD therapeutics has received little attention. This review highlights the functional roles of EGFR and EGFR TKIs in cancer and AD. Specifically, EGFR upregulation induces various types of cancer and promotes Aβ pathology. EGFR inhibition has promising effects on both diseases, including inhibiting cancer cell migration and AD pathology (e.g., Aβ, neuroinflammation, and cognitive function). The literature and our findings suggest that anti-cancer drugs can be regarded as candidates for repurposing as AD treatments. However, the direct relationship between EGFR and AD, the effects of EGFR on tau pathology in mouse models of AD, and the mechanisms of action of EGFR in the brain are still unclear. Moreover, the effects of EGFR TKIs on AD pathology have not been well examined. Further studies are required to address these issues and may provide significant insights into cancer therapy and AD progression.