Strategies to Overcome Intrinsic and Acquired Resistance to Chemoradiotherapy in Head and Neck Cancer

Abstract

Definitive chemoradiotherapy (CRT) is a cornerstone of treatment for locoregionally advanced head and neck cancer (HNC). Research is ongoing on how to improve the tumor response to treatment and limit normal tissue toxicity. A major limitation in that regard is the growing occurrence of intrinsic or acquired treatment resistance in advanced cases. In this review, we will discuss how overexpression of efflux pumps, perturbation of apoptosis-related factors, increased expression of antioxidants, glucose metabolism, metallotheionein expression, increased DNA repair, cancer stem cells, epithelial-mesenchymal transition, non-coding RNA and the tumour microenvironment contribute towards resistance of HNC to chemotherapy and/or radiotherapy. These mechanisms have been investigated for years and been exploited for therapeutic gain in resistant patients, paving the way to the development of new promising drugs. Since in vitro studies on resistance requires a suitable model, we will also summarize published techniques and treatment schedules that have been shown to generate acquired resistance to chemo- and/or radiotherapy that most closely mimics the clinical scenario.

Keywords: acquired resistance; chemoradiotherapy; chemoresistance; head and neck; intrinsic resistance; radioresistance.

Figure 1

Global picture of the different resistance mechanisms: (A) Decreased intracellular cisplatin concentration caused by increased expression of cisplatin transporters. (B) Increased expression of anti-apoptotic proteins leads to a lack of cytochrome C release. (C) Increased antioxidant content results in the sequestration of cisplatin and degradation of toxic peroxides. (D) Metabolism change driven by the Warburg effect. (E) Metallothioneins chelate Zn²⁺ ions, which are essential for p53 functions, thereby preventing apoptosis through p53 activation and cisplatin sequestration. (F) Increased expression of DNA repair machinery components resulting in less persistent DNA damage and restoration of DNA integrity instead of apoptosis. (G) General properties of stem cells such as increased expression of glutathione and anti-apoptotic protein expression as well as general slower cell cycling. (H) Epithelial to mesenchymal transition (EMT)-induced expression of SNAIL, SLUG and SMUC inhibits p53, triggering Wnt signaling, which increases DNA repair. Moreover, TWIST activation inhibits apoptosis. (I) Several microRNAs, such as miR23a, miR96-5p, miR-21 and miR 210, confer resistance through many different signaling pathways such as PTEN, HIF1 and TWIST. (J) Chemotherapy and/or cytokines in the tumor microenvironment (TME), such as IL-6, influence the cellular characteristics of the cell, inducing its survival as well as the extracellular matrix preventing proper diffusion of both oxygen and cisplatin into the cell.