squamous cell carcinoma of the head and neck ( hnscc ) is a heterogeneous disease that includes tumors arising from the mucosal epithelial surface of the oral cavity , oropharynx , hypopharynx , and larynx . although these tumors originate within different anatomic sites within the upper aerodigestive tract , they are histologically identical ( 95% of hnscc are squamous cell carcinomas ) , share common etiologic risk factors and overlapping metastatic target site profiles ( reviewed in [ 13 ] ) .
recent genetic analysis of human head and neck tumors has revealed common molecular alterations including p53 mutation , p14arf , and p16 methylation , as well as cyclin d and egfr amplification [ 36 ] . despite these similarities ,
the distinct anatomic subsites are associated with differing rates of regional metastasis  for example , vocal cord lesions tend to metastasize less frequently than oropharyngeal or hypopharyngeal lesions . this variation may be attributed to differing densities of lymph draining vessels within each of the relevant subsites .
patients who exhibit metastases into the regional nodal basin exhibit a 50% decrease in survival irrespective of treatment [ 715 ] .
currently , it is the 5th leading cause of cancer by incidence and the 6th leading cause of cancer mortality in the world [ 16 , 17 ] .
recurrent and/or metastatic hnscc patients have a poor prognosis , with a median survival of less than 1 - 2 years [ 18 , 19 ] .
several lines of evidence indicate that cancer is a disease resulting from dynamic changes in the genome that promote the progressive transformation of normal human cells into highly malignant derivatives [ 20 , 21 ] . during this process ,
cancer cells acquire several unique capabilities including self - sufficiency in response to growth signals , insensitivity to antigrowth signals , evasion of programmed death ( apoptosis ) , limitless replicative potential , sustained angiogenesis as well as invasion and metastasis , reprogramming of energy metabolism , and avoiding immune destruction [ 21 , 22 ] .
detailed global genomic analyses of several human tumors has revealed that certain classes of signaling proteins appear to be targeted more frequently by oncogenic mutations .
receptor tyrosine kinases ( rtks ) are a good example . of the 59 transmembrane rtks identified to date ,
dysregulation of ~30 rtks are associated with neoplastic transformation and cancer progression [ 2325 ] .
interestingly , ninety percent of primary head and neck squamous cell cancers , irrespective of subsite , have alterations in members of the epidermal growth factor ( egf ) family of receptor tyrosine kinases ( erbbs ) , in particular erbb1/egfr .
ten to fifteen percent of tumors will also have an alteration in another egfr family member , the erbb2/her2/neu receptor [ 27 , 28 ] .
these findings suggest a strong etiologic role for rtk dysregulation in this type of tumors . given this association , patients with head and neck squamous cell cancers are well positioned to benefit from existing and future molecular targeted agents directed against oncogenic rtks such as egfr ( reviewed in ) .     
rtks are a family of transmembrane proteins that mediate many important physiological processes in both normal and cancerous cells .
ligand binding to the extracellular domain of rtks induces receptor dimerization and activation of rtk activity .
subsequent autophosphorylation of the receptor at specific tyrosine residues within the cytoplasmic domain generates binding sites for proteins that relay downstream biological signals to regulate protein function , protein - protein interactions , and gene expression . under physiological conditions ,
rtk dysregulation can occur through several mechanisms including gene amplification or rtk overexpression , chromosomal translocation to produce constitutively active rtks , gain of function mutations or deletions that promote ligand - independent rtk activity , escape from negative regulatory mechanisms or local environmental changes , all of which lead to potent oncogenic signaling and hence neoplastic growth .
these complex signaling networks use multiple factors to drive the outcome of rtk signaling . although often depicted as linear pathways , they actually represent an integrated network with various modes of cross - talk , overlapping and distinct functions .
known signaling pathways involved in head and neck tumorigenesis include the phosphatidylinositol-3-kinase ( pi3k)-akt - mammalian target of rapamycin ( mtor ) , signal transducer and activator of transcription ( stats ) and raf kinase - mitogen - activated protein kinase kinase ( mek)-p42/p44 mitogen activated protein kinase ( mapk ) signaling pathways [ 1 , 30 ] .
this review highlights three rtk signaling pathways involved in head and neck squamous cell carcinoma ; egfr , the type 1 insulin - like growth factor receptor ( igf-1r ) and the hepatocyte growth factor ( hgf ) receptor ( met ) .
this short review will explore the relative contribution of each signaling axis to disease progression , potential modes of cross - talk , and targeted clinical approaches under investigation for disease management .
the egfr family of rtks is comprised of four different receptors known as erbb1 ( also referred to as egfr ) , erbb2 ( her2/neu in rodents ) , erbb3 ( her3 ) , and erbb4 ( her4 ) ( reviewed in [ 3133 ] ) . each receptor , with the exception of erbb3 , contain an intracellular tyrosine kinase domain that is activated by binding to extracellular egf - like ligands , which result in receptor dimerization and hence activation of downstream signaling cascades including mapk , pi3k / akt and stat signaling .
eleven egf - like ligands have been identified to date that can be categorized into four groups  those that bind egfr only ( egf , transforming growth factor alpha ( tgf ) , and amphiregulin ) , those that bind to egfr and her4 ( heparin binding - egf , betacellulin and epiregulin ) , those binding directly to either her3 and her4 ( neuregulin 1 and neuregulin 2 ) and her4 binding only ( neuregulin 3 and neuregulin 4 ) ( reviewed in ) .
epigen , the most recently discovered member of the egf - like ligand family appears to be a low affinity and broad specificity ligand that effectively activates egfr .
erbb2 is considered a ligand - less coreceptor as it does not have any known ligands that bind directly with high affinity , despite its established role as a potent oncogene in several cancer types including breast , colorectal , nonsmall cell lung carcinoma ( nsclc ) and hnscc [ 36 , 37 ] .  
aberrant egfr activity has been strongly linked to the etiology of 5890% of hnscc [ 26 , 38 ] .
these rates can vary due to the inclusion of cancers from different subsites within the head and neck , methods used to assess gene amplification and tumor scoring methods . in contrast to lung adenocarcinomas in which activating egfr mutations result in ligand - independent signaling [ 3943 ] , such activating egfr mutations are infrequent in hnscc [ 44 , 45 ] .
egfr gene amplification resulting in upwards of 12 copies per cell has been reported in hnscc patients compared to copy numbers detected in normal mucosa from noncancer patients .
this and other pathways of ligand - independent receptor activation that do not require egfr overexpression have been characterized as the likely drivers of egfr activity in hnscc .  
egfr gene amplification remains a strong indicator for poor patient survival , radioresistance , and locoregional failure [ 4749 ] .
egfr overexpression is detected in healthy mucosa in cancer patients ( field cancerization ) that will increase in proportion to observed histological abnormalities such as hyperplasia , carcinoma in situ and invasive carcinoma , indicating that it is an early event in hnscc .
accordingly , significant effort has focused on egfr signaling as a therapeutic target for treating hnscc patients .
cetuximab , matuzumab and nimotuzumab represent humanized antiegfr antibodies , whereas gefitinib and erlotinib are small tyrosine kinase inhibitors ( tkis ) ( figure 1 ) .
cetuximab ( erbitux ) competitively inhibits endogenous ligand - binding to egfr and thereby inhibits subsequent receptor activation [ 5053 ] .
cetuximab is a valuable treatment option in head and neck patients as it synergizes with current treatment modalities .
cetuximab enhances the effects of many standard cytotoxic agents , including cisplatin ( the conventional platinum - fluorouracil chemotherapeutic ) , and in combination with chemotherapy it can elicit antitumor responses in tumors that previously failed to respond to that chemotherapy .
notably , cetuximab did not dramatically exacerbate the common toxic effects associated with radiotherapy of the head and neck , including mucositis , xerostomia , dysphagia , pain , weight loss , and performance status deterioration .
cetuximab has been approved for use in combination with radiation for treating patients with locally advanced hnscc   and as monotherapy for patients with recurrent hnscc .
matuzumab ( formerly emd 72000 ) binds to egfr with high specificity and affinity to block receptor signaling , and also modulates antibody - dependent cellular cytotoxicity ( adcc ) when combined with cetuximab [ 5860 ] .
phase i clinical trials report excellent antitumor activity of matuzumab against several human tumor types including head and neck cancers .
a randomized phase iib , four - arm , open - label study recently assessed the safety and efficacy of nimotuzumab in combination with radiation therapy ( rt ) or chemoradiation therapy ( crt ) in patients with advanced ( stage iii or iva ) hnscc .
the addition of nimotuzumab to both the radiation and chemoradiation regimens was reported to improve the overall response rate , survival rate at 30 months , median progression - free survival and median overall survival .
a combined group analysis of the nimotuzumab arms versus the non - nimotuzumab arms demonstrated a significant difference in overall survival favoring nimotuzumab .
this study is compelling as patient response rates compare favorably with studies combining cetuximab with radiotherapy , but with fewer side effects .
gefitinib ( iressa ) is a small molecule tki - targeted to the intracellular active site for phosphorylation that has been tested in clinical trials involving hnscc patients , as a single agent or in combination with radiation treatment .
unfortunately , gefitinib has shown limited clinical efficacy with response rates of 1015% [ 63 , 64 ] .
erlotinib is a selective inhibitor of the egfr that also shows antitumor activity in hnscc comparable to standard combination chemotherapy .
another promising rtk under preclinical and clinical evaluation for head and neck cancers includes the igf-1r ( reviewed in [ 66 , 67 ] ) .
two ligands , insulin - like growth factor 1 ( igf1 ) and igf2 bind to igf-1r .
ligand binding to the igf-1r stimulates its intrinsic tyrosine kinase activity , activating downstream signaling networks including ras - raf , mapk and erk , and pi3k ( figure 1 ) to drive cellular functions such as cell growth , survival and differentiation .
it is widely accepted that the igf - axis activates antiapoptotic signaling , which in turn upregulates the pi3k - akt and mapk pathways in cancer cells .
additionally , igf - ir also regulates vascular endothelial growth factor ( vegf ) production , suggesting a role in tumor angiogenesis .
several studies indicate that igf-1r is overexpressed and functional in 94% of hnscc patient samples [ 70 , 71 ] .
consistent with this , igf - ir signaling significantly enhances the proliferation , motility and tumorigenicity of human head and neck cancer cell lines . igf-1r
down regulation in a hnscc cell line using antisense oligonucleotides resulted in a dose - dependent decrease in cellular proliferation , induction of apoptosis , caspase activation and reduced expression of proangiogenic cytokines such as vegf .
interest in targeting the igf-1r in hnscc was bolstered by the observation that treatment of head and neck cancer cells with either igf or egf resulted in igf - ir and egfr heterodimerization [ 71 , 72 ] .
however , only igf resulted in the phosphorylation of both receptors . using a mouse xenograft model for hnscc , treatment with antibodies against igf-1r , egfr or
it remains to be determined whether cellular cross - talk between igf-1r and egfr has an important role in determining the biological aggressiveness of hnscc or resistance to egfr - targeted therapies .  
several monoclonal antibodies and tkis for igf-1r have been tested in preclinical studies and early phase clinical studies .
however , the efficacy of igf-1r - targeted therapy for treating patients with hnscc , particularly cross - talk with egfr , warrants further investigation . to date , the effect of blocking oncogenic igf-1r and egfr signaling have been studied more extensively in breast cancer cell lines [ 7375 ] .
treatment with gefitinib and ag1024 , a tki for igf-1r reduced cell proliferation when used as single agents and showed an additive effect when used in combination [ 76 , 77 ] . targeting igf-1r and egfr signaling is currently under evaluation in hormone - sensitive metastatic breast cancer using the igf-1r inhibitor osi-906 and the egfr tki erlotinib , although results are not yet available ( http://www.clinicaltrials.gov/ , identifier nct01205685 ) . similarly , an exploratory study to assess the modulation of biomarkers in hnscc patients treated preoperatively with cetuximab and/or imc - a12 , a humanized antiigf-1r monoclonal antibody is currently underway ( http://www.clinicaltrials.gov/ , identifier nct00617734 ) .
these studies will be critical for evaluating whether the use of anti - igf-1r and egfr - targeted treatments will be more effective than single - agent modalities for treating patients with hnscc .
the met receptor is a single pass transmembrane protein that upon binding its ligand hgf  also known as scatter factor - promotes increased cell proliferation , survival and motility ( reviewed in [ 78 , 79 ] ) .
hgf is the only physiological ligand for met and is secreted as an inactive precursor polypeptide chain by mesenchymal cells .
hgf is proteolytically cleaved to form an active / heterodimer by a number of serine proteases including urokinase plasminogen activator ( upa ) , tissue - type plasminogen activator ( tpa ) , coagulation factors x. xi and xii .
met is a disulphide - linked / heterodimer derived from the proteolytic cleavage of a 170  kda precursor .
the  chain and n - terminal region of the -chain form  sema domain , a seven -propeller structure in which blades 2 and 3 bind to hgf .
the sema domain is flanked by a cysteine - rich region followed by four immunoglobulin repeats .
it is proposed that the cysteine - rich region and immunoglobulin repeat domains undergo a conformational change following hgf binding allowing for met dimerization [ 80 , 81 ] .
binding of hgf to met results in receptor autophosphorylation at key catalytic residues and subsequent recruitment of several cytosolic signaling molecules that are shared with the egfr and igf-1r signaling pathways , including the grb2/sos complex , the p85 regulatory subunit of pi3k , gab1 and jak / stat3 ( figure 1 ) .
subsequent activation of the mapk and jun - n - terminal kinase ( jnk ) pathways is responsible for the mitogenic and motogenic properties of met / hgf signaling resulting in  invasive growth  , depending on the physiological setting .
increased met signaling in human cancers can be the result of enhanced ligand - binding ( autocrine and paracrine ) , met overexpression or missense mutations that often induce constitutive kinase activity , failure of met down regulation and interactions with other cell surface receptors such as egfr ( reviewed in [ 8284 ] ) . met is overexpressed in 84% of hnscc patient samples .
interestingly , amplification of the met gene ( > 10 copies per cell ) is present only in 3 of 23 ( 13% ) tumor tissues .
hgf overexpression is detected in 45% of hnsccs , suggesting that hgf functions predominantly in a paracrine manner to drive met signaling in these cancers .
moreover , high levels of hgf are detected in hnscc patient plasma samples   supporting the idea that ligand availability is not a limiting factor for met activation .
mutations in the met ligand - binding domain ( t230m / e168d ) , transmembrane or jm domain ( r988c , t1010i ) and the tyrosine kinase domain ( t1275i , v14333i ) have also been identified in hnscc tumor samples , although their relative contribution to hnscc progression remains to be determined .
two somatic met mutations have been detected in hnscc that result in constitutively active receptor signaling that confers an invasive phenotype when ectopically expressed in cell lines .
the y1230c mutation confers anchorage - independent growth and an invasive phenotype in transfected cells , whereas the y1235d met mutation stimulates epithelial cells to invade reconstituted basement membrane in the absence of hgf . in the case of the mety1235d mutation
, genomic analyses of hnscc patient samples detected the presence of this mutant allele in 50% of metastatic tumors versus 26% in primary tumors , raising the possibility that this could be a critical genetic lesion for the acquisition of a metastatic phenotype .
alternatively , increased met signaling could afford hnscc a selective advantage for growth and/or survival in metastatic sites , such as the lymph node and lung .
indeed several studies indicate that met overexpression correlates highly with lymph node metastasis , pathologic stage , and disease reoccurrence [ 8891 ] .
moreover , patient survival was significantly reduced in biopsy samples with positive met expression relative to negative met expression , suggesting the association of met with hnscc disease progression .
consistent with these findings , treatment with the tki pf-2341066 caused a significant reduction in tumor growth , a high level of apoptosis and cellular debris within the tumor using a xenograft animal model for hnscc .
selective inhibitors of met / hgf signaling include humanized monoclonal antibodies for hgf and met , and small - molecule tyrosine kinase inhibitors directed against met ( figure 1 ) .
although their efficacy for treating a variety of solid tumors is increasingly recognized , we await results of preclinical and clinical trials for head and neck cancer that are ongoing .
the humanized antibody amg 102 shows high potency towards the mature and processed form of hgf with no detected effects on proteolytic activation of prohgf .
amg 102 interferes with met signaling , by competing with hgf for binding to the  chain of the met receptor . in phase
i clinical studies in patients with advanced solid tumors , 70% of patients had a best response in terms of achieving stable disease [ 93 , 94 ] .
importantly , no antiamg 102 antibodies were detected and circulating hgf levels were dose dependent .
another promising clinical therapeutic is the one - armed 5d5 humanized antibody ( oa5d5/metmab ) directed against met .
metmab binds met with high affinity , preventing hgf binding , met phosphorylation , receptor internalization and downstream signaling events and has been shown to inhibit tumor growth in animal models by more than 95% [ 95 , 96 ] .
metmab is currently in phase i / ii human clinical trials in comparison with erlotinib in patients with nsclc ( http://www.clinicaltrials.gov/ , identifier nct00854308 ) .
future clinical trials will be required to determine the suitability of amg102 and metmab as either single agents or combinatorial therapeutics for treating hnscc patients .
foretinib ( formerly xl880 ) is a tki whose primary targets include met and vegf , and to a lesser extent the platelet - derived growth factor ( pdgf ) receptor , ron , kit and tie2 rtks .
foretinib recently completed phase ii clinical trials in head and neck patients ( http://www.clinicaltrials.gov/ , identifier nct00725764 ) .
interim results suggest that after 12 months , 12 of 18 patients had stable disease .
a phase i dose - escalation study of the safety and pharmacokinetics of xl184 administered orally to patients with advanced malignancies ( showed that , on average , patients survived for more than 3 months with several up to 6 months while on treatment ) ( reviewed in ) . due to
encouraging data from this study , a randomized phase iii trial of xl184 in hnscc patients was initiated to investigate xl184 as a first - line treatment ( compared with placebo ) for survival benefit to patients with hnscc ( http://www.clinicaltrials.gov/ , identifier nct00704730 ) .
arq197 ( arqule ) is a nonatp - site competitive , selective small molecule inhibitor of the met intracellular region .
although the mechanism of arq197 is presently unknown , the results of phase i trials suggest potential antiinvasive activity for this compound .
overall , met , and hgf - targeted therapies have been well tolerated in clinical trials with negligible toxicities .
however , it remains to be determined whether met is a better therapeutic target than hgf .
clearly , in patients where met is activated by autocrine hgf secretion , both hgf and met targeted therapies may prove to be more efficacious treatment options .
acquired resistance is likely the result of several mechanisms including ( 1 ) egfr mutations initially present as well as those acquired during therapy , ( 2 ) receptor independent activation of downstream signaling cascades , ( 3 ) cross - talk with other rtks and converging signaling pathways and ( 4 ) environmental factors including inflammatory agents and viral infection .
resistance to cetuximab has been associated with the coexpression of the truncated egfr mutant , egfrviii with wild - type egfr .
egfrviii is the result of an in frame deletion of exons 27 spanning the extracellular ligand - binding domain .
the deletion results in a truncated egfr receptor that signals in a ligand - independent manner .
egfrviii expression has been detected in 42% of hnscc patient samples , and closely correlates with increased hnscc cell proliferation in vitro and increased tumor growth using in vivo xenograft models .
egfrviii preferentially activates the pi3k pathway instead of the ras / raf / mek pathway , which is activated by wild - type egfr . of particular interest to the therapeutic treatment of hnscc ,
egfrviii expression decreases the proliferative response of egfr expressing tumor cells to cetuximab treatment relative to vector control cells . in a recent study ,
egfrviii cells were shown to be resistant to the antiinvasive effects of cetuximab due to an increase in phosphorylation of stat3 rather than increased pi3k signaling .
egf - induced expression of the stat3 target gene hif1 was abolished by cetuximab in hnscc cells expressing wild - type egfr under hypoxic conditions , but not in egfrviii - expressing hnscc cells [ 102 , 103 ] .
these data suggest a role for egfrviii in mediating hnscc resistance to cetuximab .   despite egfrs critical role in the development of hnscc
, clinical data indicate modest clinical benefits for locoregional control and survival of head and neck cancer patients treated with egfr - targeted therapies .
hnscc patients resistant to cetuximab , often succumb to local tumor recurrence as well as regional and distant metastasis .
the addition of cetuximab to radiation therapy was reported to show improved locoregional disease control , progression - free survival , and overall survival in patients with locally advanced hnscc .
however the data revealed a disproportionate benefit of cetuximab with radiotherapy to oropharyngeal cancer patients when compared to patients treated with hyperfractionated radiotherapy .
accumulating evidence suggests that human papilloma virus ( hpv ) 16 status ( hpv+ ) is an important prognostic factor associated with a favorable outcome in a subset of head and neck cancers , including oropharyngeal and tonsilar cancers .
hpv+ tumors tend to have unique genetic aberrations including decreased egfr expression , whereas increased igf-1r levels characteristic of hnscc appear to be independent of hpv status .
clinically , hpv+ tumors are characterized by more favorable patient prognosis regarding disease - free survival as well as overall survival [ 104 , 105 ] , possibly as a result of increased genomic stability associated with global gene hypermethylation in hpv+ tumors .
thus it will be interesting to determine whether hpv+ status explains some of the benefits derived from the addition of cetuximab to radiotherapy in this subset of hnscc patients . at present
, there are few clinical indicators of which hnscc patients will most likely respond to egfr - targeted therapies .
accordingly , strategies to optimize egfr - targeted therapy remain an active area of research .
additional mechanisms that result in egfr activation include activating mutations in downstream signaling components or cross - talk between different rtk pathways . activating mutations in the pi3ka oncogene
occurs in 10% of hnscc tumors   whereas elevated levels of phosphorylated stat3 correlates with lymph node metastasis and poor patient prognosis [ 108110 ] .
conversely , h - ras mutations are infrequent in hnscc cases ( less than 5% ) , although a higher incidence has been detected in asian populations and correlates with areca nut chewing [ 111 , 112 ] .
met signaling has been shown to contribute to resistance in cell lines derived from multiple tumor types including breast , gastric and lung .
in one key study , nsclc with activating mutations in the egfr acquire resistance to the tki gefitinib and erlotinib , by amplification of the met gene to maintain akt and her3 signaling .
these studies underscore the role of cross - talk between rtks to preferentially signal through the pi3k - akt survival pathway as a mechanism for acquired drug resistance .
the relevance of met as a mechanism for escape from egfr - targeted therapy in head and neck cancers remains to be determined .
hypoxia results in the transcriptional upregulation of met gene expression via hif1 in a number of tumors including head and neck , often downstream of egfr signaling . in normoxia
, hydroxylation of 2 prolines in hif1 enables its binding to the von hippel - lindau tumor suppressor protein ( pvhl ) linking hif1 to a ubiquitin ligase complex . during hypoxia , minimal or no hydroxylation occurs enabling hif1 to avoid proteasomal degradation and
dimerize to other hif family members such as hif1   and coactivators , to form an active transcriptional hif complex on the hypoxia response element ( hre ) of target genes such as met .
the ubiquitin ligase catalyzes polyubiquitination of hif1 targeting it for proteasomal degradation . under hypoxic conditions ,
increased met signaling directs the invasive growth program , enabling cells to invade more oxygenated tissues .
since met has been reported to promote invasive and angiogenic effects in the tumor microenvironment , the use of hgf / met inhibitors may afford a means of impairing tissue colonization as well as tumor vascularization in head and neck cancer patients .     
studies on other solid tumor types , most notably glioblastoma , indicate a role for igf-1r upregulation in resistance to egfr - targeted therapies .
igf-1r mediates resistance to anti - egfr therapy in primary glioblastoma through the continued activation of the pi3k / akt survival pathway .
the apparent cooperation between igf-1r and egfr in promoting hnscc pathogenesis as well as resistance to egfr - targeted therapy , suggests an advantage to cotargeting these signaling axes for the treatment of head and neck cancers . to date , the effect of blocking oncogenic igf-1r and egfr signaling have been studied more extensively in breast cancer lines .
treatment with gefitinib and ag1024 , a tki for igf-1r reduced cell proliferation when used as single agents and showed an additive effect when used in combination [ 76 , 77 ] .
targeting igf-1r and egfr signaling is currently under evaluation in hormone - sensitive metastatic breast cancer using the igf-1r inhibitor osi-906 and the egfr tki erlotinib , although results are not yet available ( http://www.clinicaltrials.gov/ , identifier nct01205685 ) .
similarly , an exploratory study to assess the modulation of biomarkers in hnscc patients treated preoperatively with cetuximab and/or imc - a12 , a humanized antiigf-1r monoclonal antibody is currently underway ( http://www.clinicaltrials.gov/ , identifier nct00617734 ) .
these studies will be critical for evaluating whether the use of antiigf-1r and egfr - targeted treatments will be more effective than single - agent modalities for treating patients with hnscc .
targeted therapies that block egfr , met , and igf-1r signaling in head and neck cancers continue to show promising results in preclinical studies and clinical trials .
however , it is difficult to predict which patients are most likely to benefit from these therapeutics and potential side effects during long - term in vivo use . given the interplay between these rtk signaling pathways and the mediocre results obtained with monotherapy regimens thus far , clinical trials will be required to determine how egfr- , met- , and igf-1r - targeted therapies can be used in combination in order to definitively abrogate their common downstream oncogenic signaling networks .
although gaps in our knowledge concerning the role of met and igf-1r in head and neck tumorigenesis , as well as acquired resistance to antiegfr therapies remain to be addressed , efforts to translate current information towards clinical applications continue to be impressive .
 molecular therapeutics for treating epidermal growth factor receptor-(egfr- ) expressing cancers are a specific method for treating cancers compared to general cell loss with standard cytotoxic therapeutics .   
 however , the finding that resistance to such therapy is common in clinical trials now dampens the initial enthusiasm over this targeted treatment .   
 yet an improved molecular understanding of other receptor tyrosine kinases known to be active in cancer has revealed a rich network of cross - talk between receptor pathways with a key finding of common downstream signaling pathways . 
 such cross talk may represent a key mechanism for resistance to egfr - directed therapy .   
 here we review the interplay between egfr and met and the type 1 insulin - like growth factor receptor ( igf-1r ) tyrosine kinases , as well as their contribution to anti - egfr therapeutic resistance in the context of squamous cell cancer of the head and neck , a tumor known to be primarily driven by egfr - related oncogenic signals . 
1. Introduction
2. EGFR Amplification in Head and Neck Cancers
3. Targeting IGF-1R Signaling in Head and Neck Cancers
4. A Role for Met/HGF Signaling in Head and Neck Cancers
5. Understanding Resistance to EGFR-Targeted Therapies in HNSCC
6. Conclusions