Resistance to Tyrosine Kinase Inhibitors in Gastrointestinal Stromal Tumors

Abstract

Gastrointestinal stromal tumors (GIST) are the most common type of sarcoma in the gastrointestinal tract. Surgery is the primary treatment modality, but many patients suffer disease recurrence or metastasis. Fortunately, the management of advanced GIST has been revolutionized by the use of small molecule kinase inhibitors that target the underlying pathogenetic mutant kinases found in the vast majority of cases. Approximately 85% of GISTs have oncogenic mutations in KIT, allowing for constitutive kinase activation that is responsible for cellular proliferation and survival. About 5 to 7% of GISTs have activating mutations of the homologous platelet-derived growth factor receptor alpha (PDGFRA) kinase. The progression-free and overall survival of patients with advanced disease is greatly improved by treatment with the kinase inhibitors imatinib and sunitinib. However, the emergence of drug-resistant tumor clones limits the long-term benefit of these drugs in most patients. Resistance to these kinase inhibitors is associated with distinctive clinical and molecular features, with the development of secondary mutations of the oncogenic kinase being the most common mechanism. We review the molecular basis of GIST response and/or resistance to TKIs, and discuss strategies to prevent and/or overcome drug resistance. The implementation of tyrosine kinase inhibitor (TKI) therapy has revolutionized the treatment of gastrointestinal stromal tumors (GIST). Currently, imatinib is approved for first-line therapy and sunitinib is approved for imatinib-resistant GIST. Unfortunately, similar to the experience using TKIs to treat other cancers, the emergence of drug-resistant GIST is becoming a problem for many patients, and there is a clear need for more agents and other approaches to the treatment of advanced GIST (1-5). Here, we review current knowledge on the response of GISTs to TKI therapy and the mechanisms by which resistance develops. Alternative targets and therapeutic options for patients with imatinib + sunitinib-resistant GIST are discussed.

Expression profiling of GIST: CD133 is associated with KIT exon 11 mutations, gastric location and poor prognosis

“…45,46 Secondary imatinib resistance is usually caused by additional mutations in KIT (exon 13,14,17,18) or PDGFRA. In case of imatinib resistance, sunitinib is the natural first choice.…”

The Heat Shock Protein 90 Inhibitor IPI-504 Induces KIT Degradation, Tumor Shrinkage, and Cell Proliferation Arrest in Xenograft Models of Gastrointestinal Stromal Tumors

“…Eventually, sunitinib also ceases to be effective, leaving GIST patients without approved alternative treatment options. Resistance to TKIs is either preexisting or acquired through the clonal evolution of cells harboring secondary mutations that hamper TKI activity, or through KIT amplification (7,8). The development of novel therapeutic strategies that are able to extend the therapeutic efficacy of TKI or to overcome the problem of intolerance or resistance to TKI is of utmost importance for GIST patients with advanced disease.…”

Molecular features and genetic markers of gastrointestinal stromal tumors

“…В исследовании in vitro показано, что при редкой мутации V559I активированный рецеп-тор KIT резистентен к иматинибу в противополож-ность распространенной мутации V559D [94]. В среднем через 24 мес (6-31 мес) после начала лечения более чем у 60 % пациентов c метастатически-ми ГИСО, содержащими мутацию в 11-м или 9-м эк-зоне гена KIT, появляется устойчивость к иматинибу [95,96]. В первую очередь это связано с появлением вторичных мутаций в 13-, 14-и 17-м экзонах гена KIT, кодирующих ТК-домены рецептора KIT, либо в 15-м или 16-м экзонах, кодирующих ТК-вставку (рис.…”

“…Вторичные мутации появляются только в прогрес-сирующих опухолях [91,95,96]. Описаны случаи по-явления 2-5 разных мутаций в метастазах у 1 больно-го, а также 2 мутаций одновременно в одном и том же метастазе, что позволило сделать важный вывод о ге-терогенности и поликлональности ГИСО [97,98].…”