Potential Repositioning of Anti-cancer EGFR Inhibitors in Alzheimer’s Disease: Current Perspectives and Challenging Prospects

Heba M. Mansour,a*y Hala M. Fawzy,a Aiman S. El-Khatibb and Mahmoud M. Khattabb

Abstract—

Clinical trials of new drugs for Alzheimer’s disease (AD) have ended with disappointing results, with tremendous resources and time. Repositioning of existing anti-cancer epidermal growth factor receptors (EGFR) inhibitors in various preclinical AD models has gained growing attention in recent years because hyperactivation of EGFR has been implicated in many neurodegenerative disorders, including AD. Many recent studies have established that EGFR inhibition suppresses reactive astrocytes, enhances autophagy, ameliorates Ab toxicity, neuroinflammation, and regenerates axonal degradation. However, there is no incontrovertible neuroprotective proof using EGFR inhibitors due to many under-explored signaling transductions, poor blood–brain barrier (BBB) permeability of the most tested drugs, and disappointing outcomes of most clinical trials. This has caused debate about the possible involvement of EGFR inhibitors in future clinical trials. In this perspective article, we recap recent studies to merge data on the neuroprotective effects of EGFR inhibition. By consequent analysis of previous data, we notably find the under-investigated neuroprotective pathways that highlight the importance of additional research of EGFR inhibitors in attempts to be repurposed as burgeoning therapeutic strategies for AD. Finally, we will discuss future prospective challenges in the repositioning of EGFR inhibitors in AD.

Key words: EGFR inhibitors, drug repositioning, Alzheimer’s disease, tyrosine kinase inhibitors, anti-cancer drugs.

INTRODUCTION

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most prevalent form of dementia. (Congdon and Sigurdsson, 2018). The root causes of AD are not clearly understood (Lee et al., 2021), and the currently available drugs do not stop or slow down the underlying neurodegenerative process (Dura˜ es et al., 2018). Many treatment strategies are being developed to target the synthesis, toxicity, and elimination of Ab and tau, but these have failed to achieve expectations in clinical trials. The discouraging findings of AD treatments underscore the need to reconsider research approaches by better evaluating the molecular pathways and intracellular signaling mechanisms implicated in AD (Yiannopoulou and Papageorgiou, 2020).
Upregulation of kinases such as cyclic AMPdependent protein kinase, cyclin-dependent kinase 5 (Cdk5), receptor tyrosine kinase (RTK), and glycogen synthase-3 kinase (Gsk-3b) cause tau hyperphosphorylation. Consequently, suppression of these kinases may be a promising path to suppress tau hyperphosphorylation. Aside from their function in tau phosphorylation, abnormally active kinases can induce neurodegeneration through a variety of other mechanisms such as Ab accumulation, neuroinflammation, oxidative stress, overactivation of GSK-3b, reactivation of astrocyte and microglia, and excitotoxicity (Congdon and Sigurdsson, 2018). Surprisingly, studies demonstrated that preformed fibrils (PFFs) of misfolded proteins such as Ab, activate epidermal growth factor receptors (EGFR) in a double transgenic mouse model and cell cultures (Wang et al., 2012a). When PFFs are compared to EGFR ligands such as epidermal growth factor (EGF) and (HB-EGF), it seems that these fibrils may increase the aggregation of the EGFR tyrosine kinase domain (EGFR-TKD), which is known to produce fibrils. Consequently, EGFR acts as an amyloidogenic receptor to ease the cellular uptake of PFFs and the seeding of misfolded proteins (Tavassoly and Tavassoly, 2021). This makes these enzymes an intriguing approach for intervention. Kinases have been examined as drug candidates in oncology for more than three decades. Clinical pipelines in other disorders are now spreading, such as inflammatory and autoimmune diseases. Kinase inhibitors research of AD seems to be lagging behind those of mentioned diseases (Ferguson and Gray, 2018). The possible commonalities between cancer and AD have prompted clinical trials in AD using different types of tyrosine kinase inhibitors (TKIs). The trials include agents such as Saracatinib, a Fyn kinase inhibitor (Van Dyck et al., 2019), Nilotinib, a Bcr-Abl tyrosine kinase inhibitor (Pagan et al., 2016), Tideglusib, a selective GSK-3 inhibitor (Del Ser et al., 2013), Neflamapimod, a P38-MAPK inhibitor (Prins et al., 2021), and masitinib, which inhibits multiple targets, including platelet-derived growth factor receptors (PDEGFR), lymphocyte-specific kinase (Lck), FAK (focal adhesion kinase), Lck/Yesrelated protein (Lyn), and Fyn (Folch et al., 2015). Supplementary Table 1 summarize the aim, results, and weak points of the above-mentioned clinical trials, providing a solid platform for assessing the potential repositioning of TKIs for the treatment of AD.

MOLECULAR PATHWAYS INVOLVED IN THE NEUROPROTECTIVE EFFECTS OF EGFR INHIBITION

Some studies have demonstrated behavioral and cognitive enhancing, anti-amyloidogenic along with autophagy enhancement effect (Wang et al., 2012b, 2017b; Mansour et al., 2021), anti-neuroinflammatory, anti-oxidant, and anti-astrogliosis (Chen et al., 2019; Mansour et al., 2021), for EGFR inhibition in different animal models of AD. It has been found that amyloid-beta 42 (Ab42)-mediated activation of EGFR, and treatment with EGFR inhibitors, gefitinib, or erlotinib rescues Abmediated memory decline in APP/PS1 double transgenic mouse and transgenic Drosophila AD models (Wang et al., 2012a). Oral administration of gefitinib for 7 days in 8-month old Tg(APPswe.PSEN1dE9) double transgenic mice rescued memory as indicated by better performance in the Morris water maze (MWM) test.
Furthermore, it has been shown that JKF-006, JKF-011, and JKF-027, EGFR inhibitors, reversed Ab42-mediated stimulation of EGFR expressing cell line. Also, administration of different doses of JKF-006, JKF-011, and JKF027 in 6-8-month-old double transgenic rats ameliorated memory loss confirmed by the MWM test (Wang et al., 2012b). Furthermore, the immunoprecipitation results revealed that Ab42 is linked to EGFR, validating the nexus between p-EGFR and amyloidogenesis (Wang et al., 2012a).
Autophagy is a process that clears damaged organelles and misfolded proteins associated with neurodegenerative disorders (Tung et al., 2012) such as NFTs in AD (Yamamoto et al., 2006). The mammalian target of rapamycin (mTOR) is a serine/threonine kinase, which controls vital cellular processes in cells including autophagy (O’ Neill, 2013). mTOR is a downstream kinase of the PI3K/Akt pathway that is activated by receptor tyrosine kinase (RTK) . Akt inhibits tuberous sclerosis complex 1/2 (TSC1/2), which is a negative regulator of mTOR (Perluigi et al, 2015). Phosphoinositide-3 kinase (PI3K) is activated by RTK leading to mTOR activation and subsequently autophagy inhibition (Axe et al., 2008). So, the inhibition of p-mTOR stimulates autophagy of toxic or damaged proteins and ameliorates the pathogenic misfolded proteins, and delays the progression of AD (Tavassoly, 2015; Dorvash et al., 2020). Expression of human epidermal growth factor receptor-2 (HER-2), a member of RTK, becomes down-regulated during adulthood. Unpredictably, hippocampal samples from postmortem AD patients showed a higher level of HER-2 relative to their control counterparts (Wang et al., 2017b). It has been verified that HER-2 can suppress autophagy via its binding with Beclin-1, and physical dissociation of Beclin-1 from the Vps34-Vps15 complex which blocks the autophagy process (Wang et al., 2017a). HER-2 is reactivated during AD, curbing the autophagy-induced clearance of the Ab. CL-387785, HER-2 blocker, inhibited P62 while increasing LC3II/ LC3-I, which leads to autophagy increase with a simultaneous clearance of Ab and amelioration of cognitive decline of APP/presenilin-1 transgenic AD mice, assuming that inhibition of HER-2 is sufficient to stimulate autophagy (Wang et al., 2017a). Also, the administration of CL387785 rescued memory impairment in double transgenic mice as compared with gefitinib. Besides, CL-387785 inhibited the processing of APP in the CG cell line, a bipotential glial cell line from rat brain, launching the proof-ofconcept for the use of HER-2-targeted drugs for AD (Wang et al., 2017b).
In 2019, Chen et al. scrutinized the anti-inflammatory actions of the EGFR inhibitor, afatinib, using primary cultured astrocytes subjected to oxygen and glucose deprivation (OGD). They demonstrated that OGD induced EGFR phosphorylation and activated downstream signaling pathways such as Akt and ERK. Furthermore, afatinib decreased astrocyte reactivity marker, glial acidic fibrillary protein (GFAP), nitric oxide synthase, cyclooxygenase-II, caspase-1, and interleukin1b levels of the treated astrocytes in the culture medium (Chen et al., 2019). Another recent study has shown that treatment with ibrutinib, an EGFR inhibitor, ameliorates Alzheimer’s behavioral and pathological changes in 5xFAD and PS19 transgenic mice. Oral administration of ibrutinib significantly enhanced the preference of 3month-old 5xFAD mice for the NOR test but did not change behavior in the Y-maze test. The neuroprotective effects have occurred via suppression of Ab, p-tau, phosphorylated cyclin-dependent kinase 5 (CDK-5), and proinflammatory cytokines. Ibrutinib blocks Ab development in the early and moderate phases of AD (Lee et al., 2021).
A recently published study has revealed that oral administration of lapatinib ditosylate, a dual EGFR/HER2 inhibitor, ameliorated cognitive impairment behavior in the D-galactose/ovariectomized AD rat model as demonstrated by enhanced memory of lapatinib-treated rats in MWM and novel object recognition (NOR) test (Mansour et al., 2021). Also, lapatinib ditosylate lowered Ab1–42, p-tau, NADPH oxidase-1 (NOX-1), P38 mitogen-activated protein kinase (P38-MAPK), tumor necrotic factor-alpha (TNF-a), GFAP, phosphorylated mammalian target of rapamycin (p-mTOR), and glutamate receptors-II (GluR-II), along with activation of neuroprotective nitrite and prosurvival pathway; PI3K/AKT/ GSK-3b. (Mansour et al., 2021). These results authenticate the anti-amyloidogenic, anti-oxidant, antiinflammatory, anti-excitatory, and neuroprotective effect of lapatinib against AD (Mansour et al., 2021) (Fig. 1).

WHAT ARE THE UNDER-EXPLORED EGFR INHIBITION-MEDIATED NEUROPROTECTIVE PATHWAYS IN AD?

In 2020, Jia et al. stated that treatment with lapatinib blocks kainic acid-induced epilepsy in mice. This effect was achieved by increasing glutathione peroxidase 4, as well as suppressing ferroptosis-mediated cell death and oxidative stress. Also, lapatinib ditosylate suppressed glutamate-mediated excitotoxicity in the ferroptosis invitro model (Jia et al., 2020). Also, following lapatinib ditosylate administration in the D-gal/OVX Alzheimer’s rat model, it lowered the induced rise of hippocampal neurotoxic GluR-II (Mansour et al., 2021). While many studies have found that ferroptosis is linked to Alzheimer’s disease Yan and Zhang, 2020, no research has looked into the possible role of EGFR in ferroptosis and glutamateinduced excitotoxicity in Alzheimer’s disease.
NADPH oxidase (NOX)-mediated oxidative stress is augmented by Ab peptides (Tarafdar and Pula, 2018). EGFR activation stimulates reactive oxygen species (ROS) production via stimulation of the PI3K pathway that in turn activates the Ras-Rac1 cascade, which ultimately activates the NOX. ROS inactivates protein tyrosine phosphatase (PTP), which is a negative regulator of EGFR,allowing sustained activation of EGFR. So, blockade of EGFR can cut this vicious circle of activation (Paletta-Silva et al., 2013). Although treatment with lapatinib ditosylate in the D-galactose/ovariectomized Alzheimer’s rat model curbed the expression of hippocampal NOX-1 (Mansour et al., 2021), the precise cellular nexus between EGFR and NOX-1 remains under-investigated. AD has a direct inter-relationship with NOX, making NOX an exceptionally promising biomarker when developing new drugs.
Another EGFR-mediated oxidative stress and axonal degeneration mechanism is the activation of the ZNRF1–AKT–GSK3b–CRMP2 pathway. The ubiquitin ligase zinc and ring finger 1 (ZNRF1) is expressed in most neurons in the CNS. Upon neuronal injury, ZNRF1 degrades AKT, suppresses GSK-3b, inhibits Collapsin response mediator protein 2 (CRMP2), and destabilizes microtubules, causing axonal degeneration in the Wallerian in-vitro model (Wakatsuki et al., 2015). Further studies are required to understand the relationship between NOX-mediated oxidative stress, EGFR, and ZNRF1 in in vivo Alzheimer’s models.

WHAT ARE FUTURE PROSPECTIVE CHALLENGES IN THE REPOSITIONING OF EGFR INHIBITORS IN AD?

Critical requirements for proof-of-concept are still unmet for the use of EGFR inhibitors, approved for oncology, in clinical trials of AD patients. Despite the positive neuroprotective effects of many EGFR inhibitors in various AD models, only two recently published studies use Blood Brain Barrier (BBB)-permeable EGFR inhibitors: lapatinib and ibrutinib (Lee et al., 2021; Mansour et al., 2021). Although erlotinib and gefitinib are used in brain metastasis, they have not shown significant and persistent effects due to their poor BBB permeability. However, lapatinib ditosylate with its lipophilic nature and low molecular weight can be expected to penetrate the BBB (Mansour et al., 2021). Also, ibrutinib crosses the BBB as measured by HPLC in the brain tissue of mice (Lee et al., 2021). This scarcity of research is regarded as a stumbling block for the potential repositioning of EGFR inhibitors in AD. So, BBB-crossing EGFR inhibitors are highly needed to target AD, raising a crucial question about the usage of the third generation of EGFR inhibitors, which are characterized by good CNS-crossing capabilities, such as AZD3759 and dacomitinib. Surprisingly, administration of AZD3759 in adult male asynuclein Parkinson’s model mice suppressed asynuclein in the striatum, which is induced by autophagy augmentation via reduction of p62 with contaminant increase of LC3-II/LC3-I ratio (Tavassoly et al., 2021), encouraging the future engagement of AZD3759, with its good BBB permeability, in establishing a diseasemodifying approach in neurodegenerative disorders.
Despite notable preclinical outcomes in experimental models, most clinical trials assessing TKIs in AD have failed, signifying the complexity of the human brain, which is particularly noticeable in neurodegenerative diseases. The disappointing findings may be driven by the fact that few studies have been conducted, and few treatment options have been investigated so far. The use of multiple-target TKIs is considered a double sword. Targeting a single kinase and its downstream signaling pathway, in particular, may not be an effective treatment approach for AD, whose etiology is complicated and multifactorial. The sequences of all kinases are highly conserved, and they all share substrate recognition patterns that result in off-target interactions with their secondary targets.
EGFR or HER-2 inhibition has good neuroprotective effects in various AD models (Wang et al., 2012a, 2017b; Lee et al., 2021), Thus, targeting multiple kinases rather than suppressing a single kinase with dual TKIs such as lapatinib ditosylate may be an intriguing approach (Mulasar et al., 2021), which is consistent with the machine learning framework that has recommended lapatinib ditosylate as a potential drug for the treatment of Alzheimer’s disease Rodriguez et al., 2021.However, the expression of HER-2 on the downstream PI3K/AKT/ GSK-3b pathway and the relevance of this important pathway to AD progression have not been explored. It would be interesting to screen for any potential EGFR inhibition-mediated epigenetic alterations in AD models. Such epigenetic changes could be biomarkers to target in future clinical trials.
Until now, AD progression could not be stopped or slowed down by any available drug. As a result, ongoing research into new therapeutic approaches, including approved oncology TKI-EGFR inhibitors with ADmodifying properties, is a critical unmet need.. Many studies have shown that inhibiting EGFR reduces reactive astrocytes (Chen et al., 2019; Mansour et al., 2021), increases autophagy (Wang et al., 2017b; Lee et al., 2021; Tavassoly et al., 2021), ameliorates Ab toxicity (Wang et al., 2012a; Mansour et al., 2021), reduces neuroinflammation (Lee et al., 2021; Mansour et al., 2021) and regenerates axonal degradation (Wakatsuki et al., 2015). Nevertheless, many EGFR downstream signaling pathways appear to be under-explored, such as the relationship between EGFR and NOX-1-mediated oxidative stress, the effect of expression of HER-2 on the PI3K/Akt/GSK-3b pathway, and the neuroprotective effects induced by EGFR inhibition through suppression of glutamate-mediated excitotoxicity. Another limitation of the repositioning of EGFR inhibitors in AD is the wide spectrum of interaction patterns (Fagiani et al., 2020). Such a wide range of interaction motifs substantially cause paradoxical side effects (SE) but also recommends the value BI-4020 of characterizing the target range of kinase inhibition to better infer their biological activity stated in experimental and clinical studies. Although there is a benefit of re-positioning of pre-exciting drugs with known safety profile, adverse effects of TKIs tested in clinical trials range from gastrointestinal effects such as saracatinib (Du et al., 2020) to paradoxical activation of oncogenic pathways such as nilotinib (Packer et al., 2011). So, the offtarget adverse effects (eg, gastrointestinal, cardiovascular, and hematologic toxicity) can not be ignored (Caldemeyer et al., 2016). Accordingly, future studies to explore and validate the safety and efficacy of EGFR and HER-2 inhibitors in AD are warranted.
In conclusion, changes in EGFR signaling are associated with the onset and progression of AD, confirming that inhibition of EGFR could be appreciated to counteract AD. As a result, we recommend that BBBpermeable TKIs be used in further research into previously unexplored mechanisms that may connect the dots and clarify how modulating downstream signaling pathways through EGFR inhibition may ratify neuroprotection. Also, we recommend that clinical trials using safe selective multiple-targeted BBB-permeable should be started to disclose the potential of EGFR inhibitors as disease-modifying approaches in AD.

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