Translational insights into gastrointestinal stromal tumor and current clinical advances

M. L. Hemming, M. C. Heinrich, S. Bauer, S. George

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract and, in the vast majority of cases, is characterized by activating mutations in KIT or, less commonly, PDGFRA. Mutations in these type III receptor tyrosine kinases (RTKs) account for over 85% of GIST cases, and the majority of KIT primary mutations respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib. However, drug resistance develops over time, most commonly due to secondary kinase mutations. Sunitinib and regorafenib are approved for the treatment of imatinib-resistant GIST in the second and third lines, respectively. However, resistance to these agents also develops and new therapeutic options are needed. In addition, a small number of GISTs harbor primary activating mutations that are resistant to currently available TKIs, highlighting an additional unmet medical need. Several novel and selective TKIs that overcome known mechanisms of resistance in GIST have been developed and show promise in early clinical trials. Additional emerging targeted therapies in GIST include modulation of cellular signaling pathways downstream of KIT, antibodies targeting KIT and PDGFRA and immune checkpoint inhibitors. These advancements highlight the rapid evolution in the understanding of this malignancy and provide perspective on the encouraging horizon of current and forthcoming therapeutic strategies for GIST.

Original languageEnglish (US)
Pages (from-to)2037-2045
Number of pages9
JournalAnnals of Oncology
Volume29
Issue number10
DOIs
StatePublished - Oct 2018

Keywords

  • Gastrointestinal stromal tumor
  • Sarcoma
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Hematology
  • Oncology

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