Abstract
Simple SummaryHead and neck cancer remains a significant burden on patients and global health systems. Traditional approaches to therapy have included surgery, and more recently radiation and chemotherapies. Targeted immunotherapies are making significant inroads into improved outcomes, but only for small subsets of patients. Our ability to develop a wider range of targeted therapies rests on our understanding of the molecular pathways involved in carcinogenesis. This review paper summaries our current knowledge of the molecular pathways and druggable targets in head and neck oncology.Head and neck cancers are a heterogeneous group of neoplasms, affecting an ever increasing global population. Despite advances in diagnostic technology and surgical approaches to manage these conditions, survival rates have only marginally improved and this has occurred mainly in developed countries. Some improvements in survival, however, have been a result of new management and treatment approaches made possible because of our ever-increasing understanding of the molecular pathways triggered in head and neck oncogenesis, and the growing understanding of the abundant heterogeneity of this group of cancers. Some important pathways are common to other solid tumours, but their impact on reducing the burden of head and neck disease has been less than impressive. Other less known and little-explored pathways may hold the key to the development of potential druggable targets. The extensive work carried out over the last decade, mostly utilising next generation sequencing has opened up the development of many novel approaches to head and neck cancer treatment. This paper explores our current understanding of the molecular pathways of this group of tumours and outlines associated druggable targets which are deployed as therapeutic approaches in head and neck oncology with the ultimate aim of improving patient outcomes and controlling the personal and economic burden of head and neck cancer.
Highlights
Head and neck cancers (HNC) and their treatment can result in significant morbidity for patients
This paper summarises the molecular pathways and druggable targets involved in head and neck cancer as a precursor to understanding current and emerging therapies in head and neck oncology, as detailed by us elsewhere [34]
As genome sequencing findings in 2011 revealed, pathway activation is frequently (6% to 20% of HNC are squamous cell carcinomas (HNSCC)) mediated by mutations in PI3KCA which codes for p110α with more than 80% of mutations occurring in exon 9 as well as mutations in exon 20 and exon 4, especially through the mechanisms of gene amplification and low-level copy number increase [15,16]
Summary
Head and neck cancers (HNC) and their treatment can result in significant morbidity for patients. The most important activated pathways are Ras/Raf/MEK/mitogen-activated protein kinase (MAPK)/ERK, phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR), and Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways [37,38] These pathways are implicated in tumour cell growth/survival, proliferation, local invasion, angiogenesis, metastasis, protein translation and cell metabolism [38,39]. As genome sequencing findings in 2011 revealed, pathway activation is frequently (6% to 20% of HNSCCs) mediated by mutations in PI3KCA which codes for p110α with more than 80% of mutations occurring in exon 9 (helical domain) as well as mutations in exon 20 (kinase domain) and exon 4, especially through the mechanisms of gene amplification and low-level copy number increase [15,16]. Their results confirmed that KRAS2 and BRAF mutations do not co-exist in HNSCC; oncogenic KRAS2 activates wild-type BRAF, but mutated BRAF does not require KRAS2 for activation, suggesting simultaneous mutations may be redundant [65]
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