The landscape of tyrosine kinase inhibitors in sarcomas: looking beyond pazopanib

Expert Rev Anticancer Ther. 2019 Nov;19(11):971-991. doi: 10.1080/14737140.2019.1686979. Epub 2019 Nov 13.

Abstract

Introduction: Tyrosine kinases are key mediators of intracellular signaling cascades and aberrations in these proteins have been implicated in driving oncogenesis through the dysregulation of fundamental cellular processes including proliferation, migration, and apoptosis. As such, targeting these proteins with small molecule tyrosine kinase inhibitors (TKI) has led to significant advances in the treatment of a number of cancer types.Areas covered: Soft tissue sarcomas (STS) are a heterogeneous and challenging group of rare cancers to treat, but the approval of the TKI pazopanib for the treatment of advanced STS demonstrates that this class of drugs may have broad utility against a range of different sarcoma histological subtypes. Since the approval of pazopanib, a number of other TKIs have entered clinical trials to evaluate whether their activity in STS matches the promising results seen in other solid tumors. In this article, we review the emerging role of TKIs in the evolving landscape of sarcoma treatment.Expert opinion: As our biological understanding of response and resistance of STS to TKIs advances, we anticipate that patient management will move away from a 'one size fits all' paradigm toward personalized, multi-line, and patient-specific treatment regimens where patients are treated according to the underlying biology and genetics of their specific disease.

Keywords: biomarkers; kinases; sarcomas; signal transduction; targeted therapy; tyrosine kinase inhibitors.

Publication types

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

MeSH terms

  • Drug Resistance, Neoplasm
  • Humans
  • Precision Medicine
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / metabolism
  • Pyrimidines / administration & dosage*
  • Pyrimidines / pharmacology
  • Sarcoma / drug therapy*
  • Sarcoma / enzymology
  • Sarcoma / pathology
  • Sulfonamides / administration & dosage*
  • Sulfonamides / pharmacology

Substances

  • Protein Kinase Inhibitors
  • Pyrimidines
  • Sulfonamides
  • pazopanib
  • Protein-Tyrosine Kinases

Grant support

The authors acknowledge the support of Sarcoma UK, Liddy Shriver Sarcoma Initiative, Wellcome Trust, Medical Research Council, National Institute of Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research (ICR), Royal Marsden Cancer Charity, Cynthia Marsh Memorial Fund, and Cancer Research UK. The views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health.