Major Molecular Signaling Pathways in Oral Cancer Associated With Therapeutic Resistance

Abstract

Oral cancer is a sub-category of head and neck cancers that primarily initiates in the oral cavity. The primary treatment option for oral cancer remains surgery but it is associated with massive disfigurement, inability to carry out normal oral functions, psycho-social stress and exhaustive rehabilitation. Other treatment options such as chemotherapy and radiotherapy have their own limitations in terms of toxicity, intolerance and therapeutic resistance. Immunological treatments to enhance the body's ability to recognize cancer tissue as a foreign entity are also being used but they are new and underdeveloped. Although substantial progress has been made in the treatment of oral cancer, its complex heterogeneous nature still needs to be explored, to elucidate the molecular basis for developing resistance to therapeutic agents and how to overcome it, with the aim of improving the chances of patients' survival and their quality of life. This review provides an overview of up-to-date information on the complex role of the major molecules and associated signaling, epigenetic changes, DNA damage repair systems, cancer stem cells and micro RNAs in the development of therapeutic resistance and treatment failure in oral cancer. We have also summarized the current strategies being developed to overcome these therapeutic challenges. This review will help not only researchers but also oral oncologists in the management of the disease and in developing new therapeutic modalities.

Vimentin Is at the Heart of Epithelial Mesenchymal Transition (EMT) Mediated Metastasis

“…Cancer stem cells (CSC) are a small population of cells capable of self-renewal, which are known to resist therapeutic interventions and immune responses. Being pluripotent, these cells can provide cellular seeds to initiate new tumours at distant sites [ 23 ]. It was proposed that EMT can transform non-CSCs into cancer stem cells, which are invariably vimentin-positive [ 24 ].…”

Targeting Stress-Response Pathways and Therapeutic Resistance in Head and Neck Cancer

“…Thus, one single strategy might not be sufficient, and increased insights to the resistance mechanisms as well as identification of biomarkers will help to design novel and optimized therapeutic strategies, which either direct against tumor cells and/or modulate tumor microenvironment. These issues are also discussed in several recent excellent reviews [ 3 , 137 – 139 ].…”

The Epithelial–Mesenchymal Transition Influences the Resistance of Oral Squamous Cell Carcinoma to Monoclonal Antibodies via Its Effect on Energy Homeostasis and the Tumor Microenvironment

“…As a molecular switch, activated K-RAS is vital for stimulating the downstream signaling cascade via the Raf/MEK/ERK and PI3K/AKT/mTOR pathways after extracellular ligands, such as EGF, bind to the membrane receptor [ 39 ]. In OSCC patients, K-RAS frequently mutates into H-RAS, although the reason for this is unknown (this mutation is frequently detected in smokers and betel quid-chewing individuals [ 40 ]). Previous studies have demonstrated that the H-RAS mutation plays a crucial role in treatment failure and the development of resistance to cetuximab in OSCC, by stimulating downstream genes like c-MYC, BCL-XL, and BCL-2 [ 41 ].…”