Activation of EGFR signaling is one of the mechanisms for resistance to RT and/or CT in HNSCC, making it the most plausible therapeutic target [
15‐
17]. Upon ligand binding (EGF or TGF α), EGFR forms a homodimer or heterodimer with other members of the Erb family (Her2/neu, Erb3, Erb4) and activates downstream signaling cascades-Ras/Raf/MAPK and the PI3K/Akt/mTOR pathways (Figure
1). The activation of these signaling events is responsible for regulating key tumorigenic processes such as proliferation, inhibition of apoptosis, cell adhesion/motility, growth and survival. Monoclonal antibodies against the extra-cellular domain of EGFR, cetuximab, pertuzumab, panitumumab and trastuzumab, used as inhibitors in monotherapy have shown limited efficacy. In a phase I/II trial, combination of cetuximab with 5-FU and carboplatin/cisplatin showed increased survival with no cumulative toxicity in recurrent HNSCC [
18]. Cetuximab acts as a tumor specific radiosensitizer [
19,
20]. EGFR inhibition by cetuximab significantly reduced tumor repopulation during fractionated RT in a xenografted human model of SCC [
21]. In contrast, trials with chemoradiation (CRT) and cetuximab in HNSCC have shown adverse events and withdrawal of the trial [
22]. Humanized antibodies- panitumumab and trastuzumab overcome the dose dependent toxicity of cetuximab but are less immunogenic and effective. Moreover, clinical trials of trastuzumab for HNSCC have reported cardiomyopathy in patients undergoing treatment. ErbB2 inhibition has been shown to activate mitochondrial apoptosis by modulating the ratio of BCL-xL and -xS, resulting in cardiomyopathy [
23], but the exact mechanism of trastuzumab induced cardiomyopathy is still unclear. Unlike monoclonal antibodies, tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib and lapatinib block the ATP pocket of EGFR, thereby inhibiting phosphorylation and down-stream signal transduction. A multicentric study showed that erlotinib was well tolerated in pretreated HNSCCs and prolonged disease free survival [
24].
Although, EGFR overexpression is observed in more than 90% of HNSCCs, yet, only a subset of these tumors show a clinically meaningful response to EGFR inhibition [
25,
26]. Potential reasons for failure of response to EGFR inhibitors include: constitutive activation of the Ras/Raf/MAPK, STAT3 and PI3-K/AKT/mTOR signaling pathways independent of EGFR by other stimuli such as hypoxia,
Ras activation or
PTEN mutation and inhibition. The presence of EGFR variant III (EGFRvIII) in HNSCCs, is also responsible for constitutive activation of downstream signaling and resistance to EGFR inhibition by monoclonal antibodies [
27]. Acquired resistance to cetuximab is accompanied by deregulation of EGFR internalization/degradation and subsequent EGFR dependent activation of HER3 [
28]. EGFR inhibition by erlotinib/gefitinib is overcome by epithelial-mesenchymal transition [
29]. Recently, Hadad et al., [
30] proposed a novel mechanism for regulation of mesenchymal phenotype and resistance to erlotinib in HNSCC cells by Delta-crystallin enhancer binding factor 1. In addition, cross-talks between EGFR and cell adhesion molecules, cytokine receptors, ion channels and G protein coupled receptor (GPCR) lead to EGFR activation [
31]. GPCR-EGFR cross-talk may play a role in development of HNSCC and account for limited efficacy of EGFR inhibitors in HNSCC. The aforementioned mechanisms might also explain why most clinical trials suggest no correlation between EGFR protein expression and response to EGFR inhibitors. Notably, favorable outcome has been associated with skin toxicity or presence of shorter EGFR intron 1 cytosine-adenine repeats [
32]. As yet, there are no proven molecular predictors of response to EGFR targeted antibodies [
33]; search for biomarkers should be extended to EGFR-activation status and key components of downstream pathways. Tumor signaling pathway components that work synergistically with EGFR or compensate for the loss of EGFR-initiated signaling are likely to be ideal targets for multi-targeted therapy. Erb family-targeted and Src family-targeted agents are in clinical development [
34].