Novel Insights into the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GIST) have emerged as a compelling clinical and biological model for the rational development of therapeutic strategies targeting critical oncogenic events over the past two decades. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial drive...

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Bibliographic Details
Published in:Targeted oncology 2017-06, Vol.12 (3), p.277-288
Main Authors: Serrano, César, George, Suzanne, Valverde, Claudia, Olivares, David, García-Valverde, Alfonso, Suárez, Cristina, Morales-Barrera, Rafael, Carles, Joan
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - therapeutic use
Biomedicine
Cyclin-dependent kinases
Drug Resistance, Neoplasm
Gastrointestinal cancer
Gastrointestinal Neoplasms - drug therapy
Gastrointestinal Neoplasms - genetics
Gastrointestinal Stromal Tumors - drug therapy
Gastrointestinal Stromal Tumors - genetics
Humans
Imatinib Mesylate - therapeutic use
Inhibitor drugs
Medicine
Medicine & Public Health
Mutation - genetics
Oncology
Protein Kinase Inhibitors - therapeutic use
Proto-Oncogene Proteins c-kit - antagonists & inhibitors
Proto-Oncogene Proteins c-kit - genetics
Review Article
Targeted cancer therapy
Tumors
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Summary:Gastrointestinal stromal tumors (GIST) have emerged as a compelling clinical and biological model for the rational development of therapeutic strategies targeting critical oncogenic events over the past two decades. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial driver for GIST tumor initiation, transformation, and cancer cell proliferation. Three tyrosine kinase inhibitors (TKIs) with KIT inhibitory activity – imatinib, sunitinib, and regorafenib – are approved to treat advanced GIST and have successfully exploited this addiction to KIT oncogenic signaling, demonstrating remarkable activity in a disease that historically had no successful systemic therapy options. However, GIST refractory to approved TKIs remain an unmet clinical need, as virtually all patients with metastatic GIST eventually progress on any given therapy. The main and best-established mechanism of resistance is the polyclonal expansion of multiple subpopulations harboring different secondary KIT mutations. The present review aims at summarizing current and forthcoming treatment directions in advanced imatinib-resistant GIST supported by a strong biological rationale.
ISSN:1776-2596
1776-260X
DOI:10.1007/s11523-017-0490-9