Safety and feasibility of targeted agent combinations in solid tumours

Nat Rev Clin Oncol. 2013 Mar;10(3):154-68. doi: 10.1038/nrclinonc.2012.245. Epub 2013 Jan 29.

Abstract

The plethora of novel molecular-targeted agents (MTAs) has provided an opportunity to selectively target pathways involved in carcinogenesis and tumour progression. Combination strategies of MTAs are being used to inhibit multiple aberrant pathways in the hope of optimizing antitumour efficacy and to prevent development of resistance. While the selection of specific agents in a given combination has been based on biological considerations (including the role of the putative targets in cancer) and the interactions of the agents used in combination, there has been little exploration of the possible enhanced toxicity of combinations resulting from alterations in multiple signalling pathways in normal cell biology. Owing to the complex networks and crosstalk that govern normal and tumour cell proliferation, inhibiting multiple pathways with MTA combinations can result in unpredictable disturbances in normal physiology. This Review focuses on the main toxicities and the lack of tolerability of some common MTA combinations, particularly where evidence of enhanced toxicity compared to either agent alone is documented or there is development of unexpected toxicity. Toxicities caused by MTA combinations highlight the need to introduce new preclinical testing paradigms early in the drug development process for the assessment of chronic toxicities resulting from such combinations.

Publication types

  • Review

MeSH terms

  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / adverse effects
  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers
  • Cardiovascular Diseases / chemically induced
  • Clinical Trials, Phase I as Topic
  • Drug Interactions
  • Drug Monitoring
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • ErbB Receptors / antagonists & inhibitors
  • Feasibility Studies
  • Forecasting
  • Gastrointestinal Diseases / chemically induced
  • Hematologic Diseases / chemically induced
  • Humans
  • Molecular Targeted Therapy*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / physiology
  • Neoplasms / drug therapy*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / adverse effects
  • Protein Kinase Inhibitors / pharmacology
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors

Substances

  • Angiogenesis Inhibitors
  • Biomarkers
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2