New targets and therapies for gastrointestinal stromal tumors

Expert Rev Anticancer Ther. 2017 Dec;17(12):1117-1129. doi: 10.1080/14737140.2017.1400386.

Abstract

The majority of gastrointestinal stromal tumors (GIST) are driven by an abnormal receptor tyrosine kinase (RTK) signaling, occurring mainly due to somatic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA). Although the introduction of tyrosine kinase inhibitors (TKIs) has revolutionized therapy for GIST patients, with time the vast majority of them develop TKI resistance. Advances in understanding the molecular background of GIST resistance allows for the identification of new targets and the development of novel strategies to overcome or delay its occurrence. Areas covered: The focus of this review is on novel, promising therapeutic approaches to overcome heterogeneous resistance to registered TKIs. These approaches involve new TKIs, including drugs specific for a mutated form of KIT/PDGFRA, drugs with inhibitory effect against multiple RTKs, compounds targeting dysregulated downstream signaling pathways, drugs affecting KIT expression and degradation, inhibitors of cell cycle, and immunotherapeutics. Expert commentary: As the resistance to standard TKI treatment can be heterogeneous, a combinational approach for refractory GIST could be beneficial. Moreover, the understanding of the molecular background of resistant disease would allow development of a more personalized approach for these patients and their response to targeted therapy could be monitored closely using 'liquid biopsy'.

Keywords: Gastrointestinal stromal tumors; KIT; platelet derived growth factor receptor alpha; resistance; targeted therapy; tyrosine kinase inhibitors.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Drug Design
  • Drug Resistance, Neoplasm
  • Gastrointestinal Neoplasms / drug therapy*
  • Gastrointestinal Neoplasms / genetics
  • Gastrointestinal Neoplasms / pathology
  • Gastrointestinal Stromal Tumors / drug therapy*
  • Gastrointestinal Stromal Tumors / genetics
  • Gastrointestinal Stromal Tumors / pathology
  • Humans
  • Immunotherapy / methods
  • Molecular Targeted Therapy
  • Mutation
  • Protein Kinase Inhibitors / pharmacology

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors