Adaptive Responses to Monotherapy in Head and Neck Cancer: Interventions for Rationale-Based Therapeutic Combinations

Trends Cancer. 2019 Jun;5(6):365-390. doi: 10.1016/j.trecan.2019.04.004. Epub 2019 May 28.


Most Phase II and III clinical trials in head and neck cancer (HNC) combine two or more treatment modalities, which are based, in part, on knowledge of the molecular mechanisms of innate and acquired resistance to monotherapy. In this review, we describe the range of tumor-cell autonomously derived (intrinsic) and tumor-microenvironment-derived (extrinsic) acquired-resistance mechanisms to various FDA-approved monotherapies for HNC. Specifically, we describe how tumor cells and the tumor microenvironment (TME) respond to radiation, chemotherapy, targeted therapy (cetuximab), and immunotherapies [programmed cell death 1 (PD-1) inhibitors] and adapt to the selective pressure of these monotherapies. Due to the diversity of adaptive responses to monotherapy, monitoring the response to treatment in patients is critical to understand the path that leads to resistance and to guide the optimal therapeutic drug combinations in the clinical setting. We envisage that applying such a rationale-based therapeutic strategy will improve treatment efficacy in HNC patients.

Keywords: cellular signaling; head and neck; monotherapy; therapeutic resistance; tumor immunity; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Adaptation, Biological* / drug effects
  • Adaptation, Biological* / radiation effects
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor
  • Clinical Trials as Topic
  • Drug Resistance, Neoplasm
  • Head and Neck Neoplasms / etiology
  • Head and Neck Neoplasms / metabolism
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / therapy*
  • Humans
  • Immunotherapy
  • Molecular Targeted Therapy
  • Radiation Tolerance
  • Radiotherapy
  • Signal Transduction
  • Treatment Outcome
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology
  • Tumor Microenvironment / radiation effects


  • Antineoplastic Agents
  • Biomarkers, Tumor