Oral cancer is diagnosed on the basis of routine visual physical examination, medical history and risk factors probing. Early-stage diagnosis and prompt referral to specialist hospitals is a crucial factor in increasing the patients' survival rate of up to 90%. Unfortunately, about 60% of oral cancers are diagnosed at advanced stages III or IV with metastasis leading to a higher mortality rate [9]. Diagnostic delays may be attributed to both patients' ignorance as well as the ignorance of health care professionals [10]. The delaying factors on the patients' behalf include late perception of the lesion or symptoms as oral cancers are mostly asymptomatic, ignoring the lesions, self-medications, fear of surgery, poor socio-economic conditions and little or no access to specialized healthcare [11]. On the professional side, the factors include improper intra-oral and extra-oral examination, delay in biopsy taking, or wrongful biopsy site selection for histopathological examination. The average delay for the initial to definite diagnosis is reported to be about 6 months [12].

Population targeted educational intervention should mainly focus on the high-risk groups. The professional educational interventions, on the other hand, should include a sound knowledge of the disease presentation, specifically on sites like gingivae, floor of the mouth, and retromolar trigone. Screening programs should also be implemented in every country at primary or the secondary care level. The use of social media and mobile apps can be beneficial for population targeted oral cancer symptoms awareness programs [13].

The stage of the disease usually determines the primary option for the treatment of oral cancer. The treatment options include surgical resection, chemotherapy, radiotherapy, immunotherapy alone or in combination [14]. Despite favorable advancements in the conventional therapeutic modalities, many disadvantages still need to be addressed; surgical resection may lead to long-lasting disfigurements, multiple corrective surgeries usually cause considerable deformities that leaves patients in psycho-social stress and isolation, whereas radio- or chemo- therapies end up with significant toxicities or treatment resistance, all compromising the patients' quality of life and well-being [15]. Also, locoregional relapse may occur after years of the treatment leading to recurrent growth of the cancers [16].

The effectiveness of different therapeutic modalities is largely dependent on the mutational profile of tumors as genetic alterations confer new oncogenic potential to cancer cells. The precise targeting of these alterations together with treatment regimen modifications decreases therapeutic resistance and may result in countless lives being saved from potential morbidity and mortality. The factors responsible for therapeutic resistance are discussed here and are summarized in Figure 1.

TP53 is a tumor suppressor gene which prevents carcinogenesis by instigating G1 cell cycle arrest. Activated p53 (protein product of TP53) is a DNA-binding transcription factor that targets different proteins that are either involved in apoptosis (e.g., Bad, Bax, Puma, Fas, Apaf1, Noxa) or can induce cell cycle arrest (e.g., BTG2, CDNK1/p21/pRb/E2F1 pathway, GADD45) and activate DNA repair mechanisms (e.g., p48, XPC, PCNA, DDB2) after exposure to UV light, ionizing radiation or other DNA-damaging agents [17]. Because radiation therapy and chemotherapeutic agents act through many of these common pathways requiring the same proteins, p53 also plays a central role in the effective response to these cancer therapies [18].

TP53 gene is reported to encode at least 15 isoforms of p53 arising through different transcription initiation sites and alternative splicing [19]. Due to this isoformic nature, the molecular mechanisms behind the role of p53 in cancer progression and therapeutic resistance are very complex. Its categorization as a single class of tumor suppressor gene is therefore not possible. Mutant p53 cannot be considered as a single entity, but a multifaceted collection of proteins, each with a unique collection of properties such as dominant-negative functionality (antimorphic), heterogeneous loss of activity, and functional gain (neomorphic) [20]. About 40–70% of oral cancers have mutations in the TP53 gene, leading to non-functioning product. More than 90% of these mutations are between exons 5 and 8 of TP53, a region where most common mutations include R175, G245, R248, R249, R273, and R282 on the DNA binding domain [21, 22]. TP53 mutations can be segregated into disruptive or non-disruptive categories [18]. Disruptive mutations comprise irregularities in the DNA binding domains or a truncated p53 due to the existence of an early stop codon; these variations cause substantial loss of function [23]. As a result, apoptosis or cell-cycle arrest is restricted leading to tumor cell survival and treatment failures. In contrast, non-disruptive mutations partly affect the normal functionality of p53. Inside cancer cells with non-disruptive mutant p53, repair of damaged DNA is insufficient however functional enough to produce heterogeneous clones of tumor cells with novel oncogenic features and therefore known as gain-of-function mutations (neomorphic). As a result, DNA damage-induced cell death via downregulation of pro-apoptotic genes and upregulation of pro-survival genes is minimized. Such gain of function mutations can also increase DNA repair, genomic instability, stimulate proliferation, invasion, migration and dysregulate metabolism, collectively leading to therapeutic resistance [24]. Disruptive and non-disruptive mutations are linked with resistance to standard anticancer drugs such as Cisplatin, EGFR-inhibitors, alkylating agents, antioestrogens, anthracyclines, and antimetabolites [21]. The mechanism of conferring drug resistance by mutant p53 in each of these drug groups is not identical and is beyond the scope of this article.

Apart from somatic and germline mutations, wild-type p53 functions can be disrupted by alterations in its regulatory pathways. Thus, understanding the mechanism(s) behind the inactivation of p53 is very important for personalized treatment strategies. The p53 levels in normal cells are well regulated. Usually, Mouse Double Minute 2 (MDM2) negatively regulates p53 by binding to its trans-activating domain (TAD) and ubiquitinylates so that it can be degraded. p53 also stimulates transcription of MDM2, hence they are balanced via negative feedback mechanism. Stress conditions such as DNA damages can alter this balance toward increased p53 levels [25]. Based on this tightly balanced negative feedback mechanism; it is understandable that any genetic polymorphism in MDM2 can also alter p53 functional levels. A number of reports have highlighted this fact in oral cancers especially via one intronic polymorphism (rs2279744) in MDM2 leading to its induced expression [26].

Retinoblastoma (RB1) is a tumor suppressor gene belonging to RB family and other members are RBL1, RBL2. Its protein product, pRb, is actively involved in the regulation of cell cycle and differentiation at the G1-S checkpoint [46]. The RB1 gene is located on the long arm of chromosome 16, an area with high degree of loss of heterozygosity (LOH) in several tumor types including oral cancers. This LOH is reportedly present in 17% of oral cancers [47]. It has been reported that loss of RB1 can enhance the sensitivity of tumor cells to genotoxic agents such as radiations and hormonal therapies [48]. Disruption of the RB1 and associated signaling pathways in oral cancer can therefore be exploited to improve the efficacy of current therapies and to explore novel therapeutic strategies. Mutations in the RB1 family members can be of germline or sporadic type however these are less frequently reported in oral cancer as compared to alterations in its signaling pathway. Frameshift mutations in 30% of HNSCCs in exons 19–22 of the RB2/p130 gene has also been reported [49] and recently a novel RB mutation 2039T>C (Ile680Thr) has been explicitly reported in oral cancer patients [50].

pRb signaling pathway is consistently abrogated in most cancers including head and neck cancers to support tumor growth and therapy failures. Members of five protein families drive this pathway forward. These are cyclin-dependent kinase inhibitor, cyclin-dependent protein kinases, D-type cyclins, pRb-family and transcription factors E2F-family (consisting of eight members and out of these, 3 members E2F1-3 preferentially bind to pRB) [51]. This pathway is crucial in the regulation of cell growth as all the members can be activated or suppressed by growth promoting or growth suppressing signals. It has been proposed that dysregulations in the RB pathway are reflected in terms of overexpression of pRb in cancers resulting in loss of tumor suppressor function. Although the exact pathogenesis for increased pRb expression and possible alterations in cancer is not clear, a number of possibilities may exist [52]. First, the overexpressed pRb may become hyperphosphorylated, which will inactivate its growth suppressing activity. pRb can exist in three forms, unphosphorylated (found in G0), hypo-phosphorylated (exists in contact-inhibited cells and in early G1) and hyperphosphorylated (inactive form in late G1, S, G2, and M phases). Therefore, in cycling cells, pRb alternates between a hypophosphorylated form, present in early G1, and hyperphosphorylated form after passage through the restriction point in late G1 and continues through S, G2 and M, phases [53]. When hypophosphorylated, pRb sequesters E2F and inhibits its activation whereas its hyperphosphorylation by cyclin-dependent kinase complexes leads to its inactivation and release of E2F. Subsequently, E2F activates its downstream target genes (c-MYC, n-MYC, CDC-2, p21WAF-1, cyclin A, c-MYB, and EGFR) involved in DNA synthesis, cell cycle and cell growth [54]. Second, the possibility of dysregulated pRb to support cancer progression is by dysregulated E2F1 (a member of E2Ffamily), leading to inhibition of self-mediated apoptosis, and via p53 mediated pathway [55]. Third, the binding of pRb to other proteins, such as MDM2, or certain DNA viral oncoproteins (hr-HPV E7 oncoprotein) may also override the tumor suppressor function of pRb [56].

CDKN2A gene encodes two proteins p16^INK4a and p14^arf, which are part of RB pathway, and they both inhibit mitosis by acting as tumor suppressors [57]. Patients harboring germline mutations in CDKN2A carry higher risk of oral cancer and melanoma [58]. There is also increased susceptibility to develop immunotherapy resistance in these patients [59]. There are limited number of clinical oral cancer studies that have explored the role of this particular gene in modulation of therapeutic response and this gap is yet to be filled. Hyperphosphorylated pRb release E2F which activates genes involved in progression of cell cycle such as cyclin A [60]. This mechanism is blocked by p16 which inhibits phosphorylation of pRb by coupling to the cyclin D1-CDK6/CDK4 complex. p14^arf, which is another isoform produced by CDKN2A inhibits MDM2 and stabilizes p53 thereby acting as a tumor suppressor [61]. Chromosomal deletion at the 9p region that involves the CDKN2A gene locus has been recognized as the most common chromosomal aberration. In addition, there are reports of somatic mutations in p16 in 21% of oral cancer samples by analyzing the TCGA database [62]. It has also been proposed that CDKN2A chromosomal abnormalities are frequently linked with cyclin D1 gene overexpression in oral cancer [63]. This supports the fact that high p16 expression has been linked to favorable prognosis in OSCC while overexpression of cyclin D1 is linked to poor prognosis. It is uncertain whether genetic modifications at the 9p21 locus (CDKN2A) by themselves are enough to initiate carcinogenesis, as these have also been identified in benign cases [62]. Moreover, genetic modifications and p16 inactivity commonly occurs through epigenetic silencing such as promoter hypermethylation reported in 80% of oral cancer [64].

Epidermal growth factor receptor (EGFR/ErbB1/HER1) is proposed as a proto-oncogene that belongs to tyrosine kinase receptor family; other members include ErbB2/HER2/Neu, ErbB3/HER3 and ErbB4/HER4. The EGFR activation requires binding of the ligand to its extracellular domain (ECD), whereas its cellular effects depend on the activation of its cytoplasmic tyrosine kinase domain [66]. Similar ligands are also released by tumor cells during cancer progression and contribute in autocrine and paracrine effects. Stimulation of EGFR may further activates PI3K/Akt, Ras/Raf/MAPK, PLC/PKC or JAK/STAT pathways involved in diverse cellular processes such as metabolism, growth, survival, apoptosis, and differentiation [67].

EGFR is an extremely polymorphic and mutation-prone gene, with more than 1,200 single nucleotide polymorphisms (SNPs) reported in the literature [68]. Somatic mutations in the EGFR are reported in over 90% of HNSCC causing persistently raised or continued EGFR signaling. Such irregular signaling is linked not only to increased growth and reduced apoptosis in tumor cells, but also induces angiogenesis and metastasis with poor prognosis [69]. A recent analysis revealed that about 2.8% of oral cancers carry mutations in the tyrosine kinase domain of EGFR [70]. Mutations in EGFR in HNSCC are scattered from exons 18 to 21. Of all the EGFR mutations, in-frame deletions in exon 19 were the most common followed by missense mutation L858R and T790M in exon 20. The EGFR mutational landscape in HNSCC has not been sufficiently evaluated globally as is reflected from very few studies on the subject [70]. A subcategory of HNSCC shows a shortened EGFR splice variant, known as EGFRvIII, in which the ligand-binding domain is modified as a result of deletion of 6–273 residues. This modification continuously stimulates the receptor even in the absence of EGF and TGF which leads to increased cell proliferation, survival, motility and invasion [71].

In addition to somatic changes, patients can show overexpression of EGFR which is associated with higher locoregional failure, suggesting that abnormal EGFR signaling can contribute to chemotherapy, radiotherapy and immunotherapy resistance [72]. There are several possible mechanisms for such resistance. First, radiations given during radiotherapy imitate ligand–receptor interaction by inducing EGFR autophosphorylation, which stimulates PI3 kinase and Ras pathways thereby supporting growth and survival of tumor cells, and eventually leading to therapy failure. Second, after Ras stimulation, the downstream MAP kinase mediates the sustained production of amphiregulin, EGF and TGF monomers that make an autocrine circuit, thus facilitating hyperproliferation [72]. Third, the overexpressed EGFR may also activate radiation-induced DNA double strand breaks via ataxia telangiectasia mutated (ATM) gene regulation that plays a crucial role in phosphorylation of the EGFR–DNA-PK-Ku complex which intermediates DSB DNA repair. These EGFR mediated signaling cascades together with the hyperactivation of the DNA repair system may lead to the therapy failure observed in cancer patients [73].

Rat sarcoma virus (RAS) is a protooncogene and its three family members are Harvey-Ras (H-Ras), Neuroblastoma Ras (N-Ras) and Kristen Ras (K-Ras having isoforms A and B) [89]. This family encodes Ras proteins having inherent guanosine triphosphatase (GTPase) activity and stimulates downstream signaling cascade via Raf-MEK-ERK, PI3K/AKT or c-Jun N-terminal kinase (JNK) pathways involved in cellular proliferation, migration, adhesion and differentiation after growth factor stimulation such as EGFR [90]. This gene and its signaling pathway is frequently mutated in oral cancer and mostly the mutations (T81C, Q61R, G12V and G13R) are reported in H-Ras [91]. These mutations are mostly reported in smokers, betel quid chewers and also show ethnic variations [90]. The studies have highlighted the role of H-Ras mutations in treatment failure or development of resistance to EGFR tyrosine kinase inhibitors such as cetuximab and erlotinib in oral cancer patients [92]. The proposed mechanism of therapeutic resistance to EGFR TKIs include constant stimulation of downstream signaling pathways by mutated RAS gene in oral cancer via special group of genes such as CCND1, c-MYC, BCL-XL and BCL-2 [93].

Aurora kinases A and B (AurkA and AurkB) are extremely preserved serine/threonine kinases that perform an indispensable and discrete function in mitosis. AurkA is essential for mitotic spindle assembly and is located to centrosomes at spindle ends throughout the prophase up to metaphase [95]. Additionally, higher expression of AurkA leads to atypical centrosome numbers and the generation of aneuploidy which can lead to cell proliferation, tumor progression, and metastasis. It has been reported that overexpression of EGFR and AurkA in tumor tissues is a risk factor associated with poor disease-free survival and therapy resistance [96]. Additionally, AurkA/AurkB and EGFR have the same downstream signaling pathways, rendering them both as a potential therapeutic target in oral cancer. AurkA is physically or functionally related to many other key targets involved in tumourigenesis, with over 60 interacting partners including NMyc, IkBa, AKT, RalA, p53, TPX2, NEDD9, survivin etc [97].

Notch family consists of four members, Notch 1 - 4. These are small proteins involved in proliferation and differentiation and self-renewal [99]. The function of Notch in tumourigenesis is intriguing and understudied, it is reported to be either oncogenic or anti-proliferative, but most of the studies have reported it to be oncogenic. Although Notch is upregulated in oral cancer [100], some studies have suggested that Notch stimulation limits proliferation and supports differentiation [99]. It is also an important signaling pathway involved in developing chemo-resistance in tumor cells through maintaining cancer stem cell population, induction of epithelial mesenchymal transition (EMT), DDR hyperactivation and angiogenesis. Down-regulation of the Notch can induce drug sensitivity and overcome therapy resistance [99, 100]. It has been described that the average mutational rate for Notch1 in oral cancer was 12.67% compared to 4% for Notch2 and Notch3. The common Notch1 mutations reported in oral cancer are missense that occur on or near the ligand binding domain (EGF repeats) or the ankyrin domains [62].

Current molecular depiction has shown that in oral cancer, PTEN/mTOR/AKT/PI3K appears to be the repeatedly dysregulated pathway and is related to chemo- and radiotherapy resistance via autophagy stimulation, angiogenesis and co-activation of linked signaling pathways [104]. Normally this pathway is vital for regulating the cell cycle and hence affects cellular quiescence, proliferation and cancer progression [105]. Autophagy is a complex protective catabolic process in a cell to induce self -digestion of organelles to maintain homeostasis and cell population [106]. Persistent autophagic signals usually lead to apoptosis and protect from carcinogenesis under normal circumstances. However, in well-established growing tumors, autophagy helps to compensate for metabolic stresses such as ischemia and nutrient deprivation by providing energy to the cancer cells through degradation and utilization of own proteins [107]. This stress tolerance mechanism in cancer cells brought through autophagy helps them to resist different anticancer agents. Inhibitors of mTOR, such as PTEN, induce autophagy whereas oncogenes that stimulate mTOR such as Ras, PI3K and AKT suppress autophagy [108]. Interestingly, genetic and microenvironmental factors influence the way cancer cells exploit autophagy for their own survival [106, 109].

Phosphoinositide 3-kinases (PI3K) are a class of enzymes playing a key role in cellular survival, growth and differentiation. It is triggered by RTK, such as EGFR. PI3K activation phosphorylates and activates protein kinase B (PKB or AKT), which is then transported to the plasma membrane [110]. AKT can have different downstream effects such as triggering the mammalian target of rapamycin (mTOR) complexes (mTORC1 and mTORC2), which can activate transcription of p70 and other signaling molecules of the PI3K pathway, including serine/threonine protein kinase SGK146. This activation further leads to a surge in protein synthesis and cell proliferation [111]. There are numerous stimuli that augment the PI3K/AKT pathway including IGF-1, EGF, insulin and sonic hedgehog (SHH) [112]. This pathway is antagonized by various factors including phosphatase and tensin homolog (PTEN). The PTEN protein behaves as a tumor suppressor through the action of its phosphatase protein product to dephosphorylate phosphatidylinositol-trisphosphate (PIP3) to PIP2 [113]. This dephosphorylation is significant because it results in inhibition of the PKB/AKT signaling pathway, which is crucial in controlling the cellular functions such as cell growth, survival, and migration. During tumor development, mutations and alterations in PTEN/PI3K/AKT/mTOR pathway lead to increased cell proliferation and reduced cell death [114]. These mutations are reported to confer drug resistance in oral cancer treatment. The reported mechanism behind drug resistance is attributed to altered MDR-1 gene activation and prolonged cell survival. Most common mutational sites are in exon 9 and exon 20 of PIK3CA in oral cancer. Frequent mutations in this gene include E542K, E545K, H1047R, H1047Y, and H1048Q [115].

During epithelial cancer progression, tumor cells lose their specific markers such as E-cadherin, cytokeratins and express mesenchymal proteins such as vimentin, fibronectin and N-cadherins to migrate to distant areas of the body. This process is called epithelial mesenchymal transition EMT [119]. After migrating to distant areas of the body, these mesenchymal cancer cells revert back to express epithelial markers through a process called Mesenchymal epithelial transition (MET) [120]. The c-MET gene encodes the “c-MET tyrosine kinase” which induces metastasis and tumor invasion [121], and may play an important role in therapeutic resistance [122]. Mutations in c-MET are not common in oral cancers (2–13%), but higher MET copy number and increased expression of its ligand, HGF, are frequent [123]. In oral cancer patients, c-Met stimulation is associated with poor outcome and reduced survival. As c-Met and EGFR have the same downstream pathways, the activation of MET-HGFR cascade may identify a therapeutic target in oral cancer especially in patients with resistance to EGFR-targeted therapies [124]. It is interesting to note that studies on the inhibition of EGFR along with c-Met have shown improved anti-tumor activity and re-sensitization of cells to EGFR targeted therapies [125].

Dysregulation of the signal transducer and activator of transcription (STAT) family has been described in both HPV positive and negative oral cancer. Higher levels of STAT3 and its effectors are proposed to intensify the metastatic potential of oral cancer, and increase its resistance to chemo-, radio- and EGFR-directed therapies [129]. STAT3 pathway is reported to be immunosuppressive and may shield tumor cells from identification and destruction by cytotoxic T lymphocytes. This is obtained by eliciting the production of cytokines, including IL-10, IL-6, TGF-β and VEGF [130]. STAT3 pathway is triggered by the upstream effects of the IL-6 cytokine receptor family, RTK such as VEGFR, EGFR, Src family kinases (SFK) and Jenus-activated kinases (JAK). Upon stimulation, nuclear phosphorylated-STAT3 activates target genes with pro-survival factors, such as survivin, cyclin D1 and BCL-XL [131, 132].

The mitogen-activated protein kinase (MAPK) pathway affects and controls the levels of different proteins intricately involved in cell growth, maturation, programmed cell death, angiogenesis and metastasis [135]. It includes four sub-mechanisms, of which the Erk1/2 pathway is considered of utmost importance. After binding of ligands (such as EGF) to their receptors, a signaling complex stimulates mitogen-activated protein kinase 3 (MAPK3/p44MAPK/Erk1) and Erk2 (MAPK1) that dissociates from the Ras-Raf-MEK-Erk1/2 complex and consequently different structural proteins, transcription factors including AP-1, NF-κB, c Myc and ETS-1 and kinases (RSK1-4, MNKs, MSKs, MK2/3/5) are phosphorylated [136]. Mutations in the members of MAPK signaling pathway have been reported to modulate the response to chemotherapies and targeted therapies [137].

FasL and its receptors (Fas, CD95) are important members of tumor necrosis factor (TNF) family, contributing to the immune regulations. The collaboration between FasL and Fas initiates the process of apoptosis [139]. FasL is overexpressed in numerous tumors, including oral cancer, and is associated with providing anti-apoptotic potential [140, 141]. Cancer cells enhance their survival chances during tumor development by diminishing their response to Fas-mediated apoptosis. Possible modes for Fas desensitization include reduced Fas protein and inhibition of binding of the stimulated receptor to the soluble Fas ligand (sFasL), or via both mechanisms. Chemotherapeutic agents leading to upregulation of matrix metalloproteinase 7 (MMP7), that causes the production of sFasL and therefore FAS/FASL mediated apoptosis is downregulated leading to therapy failure [142]. MMPs have the basic function to break down extracellular matrix (ECM) by degrading macromolecules including types I, II, IV, and V collagens, fibronectin and proteoglycan. High level of MMP7 expression accelerates cancer invasion and angiogenesis by cleavage of ECM and connective tissues. During cancer progression, MMP7 degrades cell surface proteins, promotes adhesion of cancer cells, and consequently promotes tumor metastasis [140]. A number of reports have suggested that polymorphisms in MMP3 and MMP7 are important risk factor for therapeutic resistance in cancer. For MMP7, two polymorphisms have been reported, 181A → G and −153C → T while in MMP3, the insertion or deletion of an adenine at position −1612 (−1612insA) demarcates two alleles 5A or 6A. The 6A allele is associated with reduced transcription compared with 5A. An important positive association between MMP3 6A isoform and chemotherapy sensitivity in French oral cancer patients has been reported with subjects having 6A allele responding better to 5-FU-cisplatin combination treatment [143].

In humans, there are four members of FAT family, these are FAT1 - 4 that encodes proteins Fat1−4, respectively. These proteins are involved in intercellular adhesion, morphogenesis, migration and interaction with ECM and different signaling cascades [145]. FAT1 is reported to be active in conferring cisplatin based chemotherapy resistance in oral cancer [146]. Limited studies are available on the role of this molecule in oral cancer and have shown conflicting results. These proteins are reported to be tumor suppressors via inhibition of Yes-associated protein (YAP) 1 and suppress cell growth and metastasis in oral cancer [147, 148], conversely these are also shown to be proto-oncogenic and play a role in metastasis and apoptotic suppression in different carcinomas [149]. Oncogenic potential of FAT1 may be attributed to mutational changes (nonsense, missense, and frameshift) in the gene that render it oncogenic. Studies have shown that FAT1 can be targeted to re-sensitize cells to cisplatin chemotherapy via downregulating LRP5/WNT2/GSS signaling and increased oxidative stress [146].

CASP-8 gene is primarily a tumor suppressor gene encoding procaspase-8 protein found on chromosome 2q33-34 [151]. Gene product is a cysteine endoprotease that is a key factor for functionality of apoptotic pathway when triggered by death signals [152]. Therefore, it is crucially important in tumor progression and resistance in chemo- and radiotherapy induced cancer cell death via apoptotic pathways [153]. Resistance to cytotoxic drugs due to apoptotic suppression is attributed to different mechanisms such as somatic changes (gene deletions, promoter methylation) in caspase-8, its sequestration by Bcl-2 or overexpression of its inhibitors such as FLIP (FLICE-like Inhibitory Protein). Therefore, this molecule can be targeted to restore treatment sensitivity [153]. Recently, it has been proposed that a specific mutation Gly325Ala in caspase8 gene enables it to induce NF-κB-mediated expression of different cytokines and angiogenesis. Therefore cancer cells harboring such mutation has the higher potential for growth and progression [154]. Studies have also shown that mutations in CASP-8 namely R417X (C>T), R218Q (G>A), G310D (G>A), G310D (G>A), D200fs (del TATT frameshift deletion at exon 4), E204X (G>T), Q225X (C>T), T258fs (C>T) and L428Q (T>A) affect functions of CASP-8 and these are positively correlated with cancer progression [155]. However, one single nucleotide polymorphism SNP on the CASP-8 promoter (−652 6 bp ins/del) is reported to negatively co-relate with cancer progression [156]. CASP-8 is also active in other cellular mechanisms such as autophagy, cell adhesion, migration and endosomal trafficking. These functions are reported to be hijacked by cancer cells to progress and invade multiple sites. Based on these assumptions, it is now believed that caspase-8 can behave as tumor suppressor or proto-oncogene. Therefore, new synchronized treatment strategies that raise caspase-8 level while inducing its apoptotic function should be explored [152].

Exploring the epigenetic mechanisms in cells has opened novel prospects for cancer management. The main goal is to disrupt transcriptional mechanism mediating the carcinogenesis by targeting epigenetic enzymes and thus therapeutic benefits can be derived [40]. Inhibitors of DNA methyl-transferases (DNMT) such as decitabine and 5'-azacitidine or histone deacetylases (HDAC), including romidepsin or vorinostat are FDA approved epigenetic cancer drugs [161]. Recently, the identification of loss of function alterations in epigenetic proteins has added huge difficulty in recognizing effective drug targets. The fact that epigenetic mechanisms are frequently regulated by opposite groups of enzymes or pathways may be a likely answer to this problem [62].

The repair of DSBs via NHEJ has the potential to sensitize tumor cells to chemo- and radiotherapy [170]. Different molecules targeting DDR pathway proteins are summarized in Figure 4. Oncogenesis due to MMR failure and hyperactive DNA repair pathways carry high genomic instability and generate neoantigens, therefore in such cases immune checkpoint inhibitors, such as those directing against PD-1 (pembrolizumab), or the ligand PD-L1 (MPDL3280A) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (ipilimumab), are more beneficial [172].

Evidence has suggested the possibility of observing variations in miRNA expression earlier or during therapeutic period can estimate the response to specific treatments [176]. Modulation of dysregulated miRNA by molecules that substitute downregulated miRNA or use of blockers which bind upregulated miRNA may be of future applications [173]. Currently, only one clinical study is available in liver cancer patients with MRX34, a molecule imitating miR-34. No clinical trials have been reported for oral cancer [177].

No distinguishing therapeutic targets for eliminating CSCs have been identified yet. However, different in-vitro and in-vivo studies have been reported to target critical pathways specific to CSCs such as CD44, c-MET, ALDH1 and Wnt pathways to eradicate CSCs. Radionuclide186Re-cmAb (U36) antibody to target CD44 is in phase I clinical trial in oral cancer patients [178]. Further research is urgently required to identify specific molecular targets and to develop strategies to eliminate CSCs that would curb the cancer growth.

Another survival mechanism by CSC reported recently is the reversal of apoptosis known as anastasis; when the cells revive from “the brim of death or point of no return” after the removal of the apoptosis-inducing agent [186]. The molecular analysis of anastasis has shown upregulated TGF beta, RTK, MAPK and angiogenesis inducing factors. It has been reported that anastasis may be a possible survival pathway of the CSCs to resist the apoptotic death induced by therapeutic agents. Any genetic aberrations causing anastasis in CSCs are most likely to confer additional therapeutic resistance [187].

Recent advances in the field of molecular pathology and genetics have helped better understand the complex and heterogeneous oral cancer molecular profiles. These findings are the basis of recent developments of new therapeutic agents specifically targeting critical molecules or genetic lesions involved in cancer progression and therapeutic resistance. However, there is still no consensus on the specific biomarkers that can be correlated with clinical staging, treatment efficacy and post treatment monitoring of patient recovery [188]. Many critical molecules being studied in other cancers are not being tested in oral cancer; furthermore, number of clinical longitudinal studies on the efficacy of single or combination therapies in oral cancer patients is far fewer. The main focus of the future research should be to explore complex genetic, epigenetic and microenviornmental interactions in oral cancer contributing to treatment failure especially the CSCs that are now accepted as the root cause of cancer relapse and therapeutic resistance.