ZNF-Mediated Resistance to Imatinib Mesylate in Gastrointestinal Stromal Tumor

Abstract

Although imatinib mesylate (IM) has transformed the treatment of gastrointestinal stromal tumors (GIST), many patients experience primary/secondary drug resistance. In a previous study, we identified a gene signature, consisting mainly of Kruppel-associated box (KRAB) domain containing zinc finger (ZNF) transcriptional repressors that predict short-term response to IM. To determine if these genes have functional significance, a siRNA library targeting these genes was constructed and applied to GIST cells in vitro. These screens identified seventeen “IM sensitizing genes” in GIST cells (sensitization index (SI) <0.85 ratio of drug/vehicle) with a false discovery rate (FDR) <15%, including twelve ZNF genes, the majority of which are located within the HSA19p12–13.1 locus. These genes were shown to be highly specific to IM and another tyrosine kinase inhibitor (TKI), sunitinib, in GIST cells. In order to determine mechanistically how these ZNFs might be modulating response to IM, RNAi approaches were used to individually silence genes within the predictive signature in GIST cells and expression profiling was performed. Knockdown of the 14 IM-sensitizing genes (10 ZNFs) universally led to downregulation of six genes, including TGFb3, periostin, and NEDD9. These studies implicate a role of KRAB-ZNFs in modulating response to TKIs in GIST.

KAP1 Promotes Proliferation and Metastatic Progression of Breast Cancer Cells

“…In breast cancer, three KRAB-ZNFs undergo gene amplification (31). High expression of 18 KRAB-ZNF genes have been associated with increased resistance of GIST tumors to imatinib treatment (32). However, the expression patterns and functions of the majority of KRAB-ZNFs in breast cancer are still unknown.…”

Personalized medicine: a new option for nuclear medicine and molecular imaging in the third millennium

“…Gene array data were based on tumor specimen obtained by surgery after an FDG-PET scan. FDG uptake was found to be associated with the expression of several zinc finger proteins, the expression of which was related to sensitivity to imatinib [12]; furthermore, the transport of FDG was associated with VEGF-A. These findings suggest that FDG-PET may serve as a screening tool to identify those patients with GISTs who are most likely to respond favorably to imatinib treatment.…”

“…All tumors showed significant radiopharmaceutical uptake, mainly due to an enhanced vascular fraction and increased FDG transport. Quantitative data for about 12,626 genes were obtained per gene chip; the expression values for 137 genes (1.1%) exceeded the median expression value for the reference gene, i.e. β 2 -microglobulin.…”

Drug Repurposing Identifies a Synergistic Combination Therapy with Imatinib Mesylate for Gastrointestinal Stromal Tumor

“…These discoveries have led to the unprecedented disease control of advanced GIST with the introduction of the kinase inhibitors imatinib mesylate, sunitinib malate, and regorafenib (6–22). However, the success of imatinib in GIST has been tempered by the fact that the treatment only increases the median time to tumor progression by approximately two years (6, 11–23). Therefore, it is clear that additional therapeutic approaches are needed.…”