QbD-based co-loading of paclitaxel and imatinib mesylate by protamine-coated PLGA nanoparticles effective on breast cancer cells.

Aim: Paclitaxel and imatinib mesylate are drugs used in the treatment of breast cancer. Conventional drug-delivery systems have limitations in the effective treatment of breast cancer using the drugs. Materials & methods: Combination index studies were used to identify the optimum ratio of both drugs showing maximum synergistic effect. Using a systematic quality-by-design approach, protamine-coated PLGA nanoparticles co-loaded with paclitaxel and imatinib mesylate were formulated. Further characterization and cell line evaluations were performed. Results: Encapsulation efficiency obtained was 92.54% for paclitaxel and 75.12% for imatinib mesylate. A sustained (24 h) and controlled zero-order drug release was obtained. Conclusion: Formulated nanoparticles had a low IC50 value and enhanced cellular uptake.

[Box: see text].

Glycolysis in gastrointestinal stromal tumor: a brief overview.

Gastrointestinal stromal tumor (GIST) is the most prevalent mesenchymal tumor of the digestive tract. Its growth is primarily influenced by mutations in KIT or PDGFRA. Surgery is the primary treatment option for GIST; however, KIT inhibitors, such as imatinib, are used for inoperable cases. Resistance to imatinib is an upcoming challenge, especially because the effectiveness of alternative drugs is limited. Enhancement of the glycolysis pathway in cancer cells has been identified as a key feature in cancer. This unique metabolic activity has implications on tumor growth, prognosis, and resistance to therapy, even in GIST. Members of the glucose transporter (GLUT) family (particularly GLUT-1) play a significant role in GIST progression and response to treatment. Diagnostic imaging using 18F-fluorodeoxyglucose positron emission tomography/computed tomography, which enables visualization of glucose metabolism, can aid in GIST diagnosis and risk assessment. The interplay between glycolysis and GIST can lead to the development of various therapeutic strategies, especially those involving glycolysis-related molecules, such as hexokinase and lactate dehydrogenase. However, further research is required to understand the full spectrum of glycolysis in GIST and its therapeutic potential. Herein, we present an exhaustive overview and analysis of the role of glycolysis in GIST, especially as a therapeutic target.

Investigating the preferential interaction between imatinib mesylate and VEGF G-quadruplex DNA as therapeutic strategies for cancer treatment: Biophysical and molecular modelling approaches.

G-Quadruplex DNA (GQ-DNA) is one of the most important non-canonical nucleic acid structures. GQ-DNA forming sequences are present in different crucial genomic regions and are abundant in promoter regions of several oncogenes. Therefore, GQ-DNA is an important target for anticancer drugs and hence binding interactions between GQ-DNA and small molecule ligands are of great importance. Since GQ-DNA is a highly polymorphic structure, it is important to identify ligand molecules which preferentially target a particular quadruplex sequence. In this present study, we have used a FDA approved drug called imatinib mesylate (ligand) which is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia, gastrointestinal stromal tumours. Different spectroscopic techniques as well as molecular docking investigations and molecular simulations have been used to explore the interaction between imatinib mesylate with VEGF GQ DNA structures along with duplex DNA, C-Myc, H-Telo GQ DNA. We found that imatinib mesylate shows preferential interaction towards VEGF GQ DNA compared to C-Myc, H-Telo GQ and duplex DNA. Imatinib mesylate seems to be an efficient ligand for VEGF GQ DNA, suggesting that it might be used to regulate the expression of genes in cancerous cells.

Oral lesions associated with imatinib mesylate therapy: five new cases and a literature review.

This study aimed to report the collective clinical characteristics of oral side effects associated with imatinib therapy according to age, sex, and clinical condition. A bibliographic review was performed using the PubMed, Web of Science, Scopus, Cochrane Library, and Embase databases. Forty-five cases of oral side effects due to imatinib therapy were identified in the literature. With the addition of five new cases seen at the authors' institution, a total of 50 cases were analysed. Of the five new cases, four with gastrointestinal stromal tumours developed oral lichenoid lesions (OLLs), and one with chronic myeloid leukaemia (CML) developed oral hyperpigmentation (OHP). Of the total 50 patients, 26 were male and 24 were female, and age ranged from 29 to 86 years. Most patients were ≥50 years old (80%); only three patients were jaw was the least common, with just five cases (10%). Among the patients with OHP, the predominant clinical condition was CML (22 cases, 91.7%). In conclusion, the possibility of oral side effects needs to be considered during the examination of patients receiving imatinib therapy.

Use of a pH-responsive imatinib mesylate sustained-release hydrogel for the treatment of tendon adhesion by inhibiting PDGFRß/CLDN1 pathway.

Adhesion after tendon injury, which can result in limb movement disorders, is a common clinical complication; however, effective treatment methods are lacking. Hyaluronic acid hydrogels are a new biomedical material used to prevent tendon adhesion owing to their good biocompatibility. In addition, potential drugs that inhibit adhesion formation have gradually been discovered. The anti-adhesion effects of a combination of loaded drugs into hydrogels have become an emerging trend. However, current drug delivery systems usually lack specific regulation of drug release, and the effectiveness of drugs for treating tendon adhesions is mostly flawed. In this study, we identified a new drug, imatinib mesylate (IM), that prevents tendon adhesion and explored its related molecular pathways. In addition, we designed a pH-responsive sustained-release hydrogel for delivery. Using the metal-organic framework ZIF-8 as a drug carrier, we achieved controlled drug release to increase the effective drug dose at the peak of adhesion formation to achieve better therapeutic effects. The results showed that IM blocked the formation of peritendon adhesions by inhibiting the PDGFRß/ERK/STAT3/CLDN1 pathway. Furthermore, the hydrogel with ZIF-8 exhibited better physical properties and drug release curves than the hydrogel loaded only with drugs, showing better prevention and treatment effects on tendon adhesion.

A Unique Case of Mesenteric Gastrointestinal Stromal Tumor Presenting as an Acute Abdomen.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract and arise from the interstitial cells of Cajal in the mesenteric plexus. These tumors can originate in any part of the GI tract; however, a higher burden has been observed in the stomach and small intestines. Mesenteric GISTs are exceedingly rare, with unique clinicopathological features and a poorer prognosis. Herein, we describe a unique case of a 66-year-old female with a remote history of appendectomy who presented to the emergency room complaining of severe abdominal pain and vomiting. On imaging, the patient was found to have a large inflammatory mass associated with small bowel loops, and the pathology confirmed a mesenteric GIST. The tumor was resected, and the genomic test results confirmed the KIT (exon 11) mutation. Although the tumor had a low mitotic rate, the tumor was large enough to warrant the initiation of adjuvant imatinib mesylate for 36 months with regular bloodwork and imaging.

Imatinib-induced dermatomyositis sine dermatitis - a rare case report.

Idiopathic Inflammatory Myopathies are rare conditions with several heterogeneous disease subtypes. They can range from limited muscle or skin involvement to severe, systemic, life-threatening disease. Although the etiology is unknown, some evidence suggests a role for external agents, particularly drugs. Herein, we present a case of a 71-year-old woman with chronic myeloid leukemia who developed imatinib-induced dermatomyositis sine dermatitis. The presentation was predominantly muscular, characterized by proximal muscle weakness and myalgia of the lower limbs, with positive anti-Mi2a antibodies. Spontaneous recovery was observed after drug discontinuation, without the need for immunosuppressive therapy. This is the first confirmed description of an imatinib-induced dermatomyositis sine dermatitis. It reflects the importance of a high awareness from rheumatologists and hematologists to accurately anticipate and identify similar situations.

Adjuvant therapy for rare rectal gastrointestinal stromal tumors: A case report.

Key Clinical Message: Anorectal gastrointestinal stromal tumors are extremely rare, constituting less than 0.1% of rectal tumors. Surgical resection using a transanal wide excision followed by adjuvant therapy with tyrosine kinase inhibitors can be a successful treatment combination to remove the mass and prevent recurrence while preserving the integrity of the anal sphincter. Abstract: Gastrointestinal stromal tumors (GISTs) are a rare subset of neoplasms, accounting for about 1%-2% of primary gastrointestinal malignancies. The stomach is the most common site for GISTs, with anorectal GISTs being exceptionally rare, representing only 0.1% of all rectal tumors. The standard approach for managing localized GIST involves complete surgical excision to achieve negative microscopic margins (R0) while preserving the tumor capsule and maintaining anal sphincter function. Surgical resection with transanal wide excision followed by adjuvant therapy using tyrosine kinase inhibitors can successfully remove the mass, prevent recurrence, and preserve the anal sphincter's integrity. Adjuvant therapy with imatinib is the recommended treatment for all localized GISTs assessed to have an intermediate or high risk of relapse. Here, we report a case of a 63-year-old male with a rectal GIST who underwent transanal wide excision followed by adjuvant therapy with tyrosine kinase inhibitors.

Advanced and Metastatic Gastrointestinal Stromal Tumors Presenting With Surgical Emergencies Managed With Surgical Resection: A Case Series.

Advanced and metastatic gastrointestinal stromal tumors (GISTs) presenting with surgical emergencies are rare. Neoadjuvant imatinib being the treatment of choice for non-metastatic advanced disease with a proven role in downstaging the disease may not be feasible in patients presenting with bleeding and obstruction. We present a case series with retrospective analysis of a prospectively maintained database of patients with advanced and metastatic GISTs presenting with surgical emergencies. Clinical characteristics, imaging and endoscopic findings, surgical procedures, histological findings, and outcomes in these patients were studied. Four patients were included in this case series, with three males and one female (age range: 24-60 years). Two patients presented with melena; one with hemodynamic instability despite multiple blood transfusions underwent urgent exploratory laparotomy for bleeding gastric GIST, while the other underwent surgical exploration after careful evaluation given the recurrent, metastatic disease with a stable metabolic response on six months of imatinib. One patient with metastatic jejunal GIST who presented with an umbilical nodule and intestinal obstruction was given a trial of non-operative management for 72 hours, but due to non-resolution of obstruction, segmental jejunal en bloc resection with the dome of the urinary bladder with reconstruction and metastasectomy was needed. The patient with advanced gastric GIST who presented with gastric outlet obstruction was resuscitated, and an attempt of endoscopic naso-jejunal tube placement was tried, which failed, and exploration was needed. The mean length of hospital stay was 7.5 days. Histopathological examination confirmed GIST in all four patients with microscopic negative resection margins. All patients were started on imatinib with dose escalation to 800 mg in the patient with recurrent and metastatic disease; however, the patient with bleeding gastric GIST experienced severe adverse effects of imatinib and discontinued the drug shortly. All four patients are disease-free on follow-ups of 15 months, 48 months for the patient with advanced non-metastatic disease, and six and 24 months for the patients with metastatic disease. In the era of tyrosine kinase inhibitor (TKI) therapy for advanced and metastatic disease, upfront surgery is usually reserved for surgical emergencies only. Surgical resection, the cornerstone for the treatment of resectable GIST, may also be clinically relevant in metastatic settings, although it requires a careful and individualized approach.

CFL1 is Implicated in Chronic Myeloid Leukemia Response during Imatinib Therapy.

Cofilin (CFL1) is one critical member of the actin deploy family (ADF). Overexpression of CFL1 is associated with aggressive features and poor prognosis in malignancies. We evaluated the expression of CFL1 in patients with chronic myeloid leukemia in the chronic phase (CML-CP), acute myelocytic leukemia (AML) and healthy controls. The role of CFL1 in imatinib therapy was also investigated using cell line. We found that the expression of CFL1 was lower in CML patients than that in healthy controls, and was significantly upregulated after imatinib therapy (p<0.05). CML patients with lower CFL1 achieved higher Major molecular response (MMR) rate after 6 months of imatinib therapy (p<0.05). Cofilin, P-cofilin and F-actin, especially branched F-actin were all upregulated after imatinib therapy. The lower CFL1 expression before treatment may predicts a better response to imatinib. Imatinib affects F-actin remodeling in CML patients by regulating CFL1 expression and activity.

Malignant rectal GIST managed with chemotherapy (Imatinib Mesylate): A case report and a comprehensive review.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors involving the gastrointestinal tract, arising from the interstitial cells of Cajal. GIST comprises about 1% of all GI tumors. Rectal GISTs are rare and comprise of approximately 5% of all GISTs and only 0.1% of rectal tumors are found to be GISTs. Rectal GISTs may be diagnosed incidentally or present with symptoms, including defecation problems, bleeding, and/or pain. We report a case of a 46-year-old male with rectal GIST metastasized to the liver and bilateral lung parenchyma managed by Imatinib Mesylate (IM) regimen. Rectal GIST although being rare, must be considered as a differential diagnosis in a patient presenting with defecatory problems with bleeding.

Chronic myeloid leukemia (CML) in children and adolescents-Clinicopathological findings.

BACKGROUND: Barely two per million Belgian children/adolescents are diagnosed with chronic myeloid leukemia (CML) annually. In this retrospective study, we aimed to investigate the diagnostic features, clinical and laboratory characteristics, and treatment outcome of this rare entity. METHODS: Medical records of all pediatric CML patients (age ≤ 17 years) diagnosed at the University Hospitals Leuven between 1986 and 2021 were reviewed. RESULTS: Fourteen patients (median age at diagnosis 12.5 years) were included, all presenting in chronic phase. Five patients were diagnosed before 2003; main therapy included hydroxyurea (n = 5/5), interferon-alfa (n = 3/5) and allogeneic hematopoietic stem cell transplantation (allo-Tx) (n = 3/5). Complete hematologic response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMR) was reached in resp. 4/5, 4/5 and in 2/3 of evaluable patients. Three patients progressed to accelerated/blast phase (median time 19 months) and 1/5 is alive and disease-free at last follow-up. Nine patients were diagnosed after 2003 and were treated with first generation (1°G) tyrosine kinase inhibitors (TKI): 3/9 subsequently underwent an allo-Tx, 4/9 were switched to 2°G TKI, one patient was additionally switched to 3°G TKI. CHR, CCyR and MMR was reached in 9/9, 9/9 and 8/9 of these patients. No progression to accelerated/blast phase was observed and none of these patients deceased. At last follow-up, 7/9 patients were in MMR or disease free, the two remaining patients did not reach or lost MMR, both related to compliance issues. CONCLUSION: Our study confirmed that TKI significantly improved the prognosis of pediatric CML. However, drug compliance poses a considerable challenge.

68 Ga-labeled, imatinib encapsulated, theranostic liposomes: Formulation, characterization, and in vitro evaluation of anticancer activity.

Cancer is still a global health problem. Among cancer types, breast cancer is the most frequently diagnosed one, and it causes a high mortality rate if not diagnosed in the early stages. In our study, imatinib encapsulated, nanosized, neutral/cationic liposome formulations were prepared as theranostic agents for breast cancer. After the characterization studies in which all liposomes exhibited proper profile owing to their particle size between 133 and 250 nm, polydispersity index values lower than 0.4, neutral and cationic zeta potential values, and high drug encapsulation efficiency, controlled drug release behaviors with zero-order kinetic were obtained. The higher than 90% radiolabeling efficiency values were obtained thanks to the determination of optimum radiolabeling condition (80°C temperature, 5 mCi radioactivity, and 10 min incubation period). According to the resazurin assay evaluating the cytotoxic profile of liposomes on MCF7 cells, neutral empty liposome was found as biocompatible, while both cationic liposomes (empty and drug-loaded ones) exhibited high nonspecific cytotoxicity at even low drug concentration due to the existence of stearyl amine in the formulations. However, dose-dependent cytotoxic effect and the highest cellular binding capacity were obtained by imatinib loaded neutral liposomes. In conclusion, 68 Ga-radiolabeled, imatinib-loaded, neutral, nanosized liposome formulation is the most promising one as a theranostic agent among all formulations.

Pharmacokinetics and pharmacodynamic evaluation of hyaluronic acid-modified imatinib-loaded PEGylated liposomes in CD44-positive Gist882 tumor-bearing mice.

To develop a PEGylated and CD44-targeted liposomes, enabled by surface coating with hyaluronic acid (HA) via amide bond to improve the efficacy of imatinib mesylate (IM), for tumor-targeted cytoplasmic drug delivery. HA was covalently grafted on DSPE-PEG2000-NH2 polymer. HA-modified or unmodified PEGylated liposomes were prepared with ethanol injection method, and the stability, drug release, and cytotoxicity of these liposomes were studied. Meanwhile, intracellular drug delivery efficiency, antitumor efficacy, and pharmacokinetics were also investigated. Ex vivo fluorescence biodistribution was also detected by small animal imaging. In addition, endocytosis mechanism was also explored HA-coated PEGylated liposomes (137.5 nm ± 10.24) had a negative zeta potential (-29.3 mV ± 5.44) and high drug loading (27.8%, w/w). The liposomes were stable with cumulative drug leakage (<60%) under physiological conditions. Blank liposomes were nontoxic to Gist882 cells, and IM-loaded liposomes had higher cytotoxicity to Gist882 cells. HA-modified PEGylated liposomes were internalized more effectively than non-HA coating via CD44-mediated endocytosis. Besides, the cellular uptake of HA-modified liposomes also partly depends on caveolin-medicated endocytosis and micropinocytosis. In rats, both liposomes produced a prolonged half-life of IM (HA/Lp/IM: 14.97h; Lp/IM: 11.15h) by 3- to 4.5-folds compared with the IM solution (3.61h). HA-decorated PEGylated liposomes encapsulated IM exhibited strong inhibitory effect on tumor growth in Gist882 cell-bearing nude mice and formation of 2D/3D tumor spheroids. The Ki67 immunohistochemistry result was consistent with the above results. IM-loaded PEGylated liposomes modified with HA exerted the excellent anti-tumor effect on tumor-bearing mice and more drugs accumulated into the tumor site.

miR-181a plays the tumor-suppressor role in chronic myeloid leukemia CD34 + cells partially via SERPINE1.

The formation of the BCR-ABL fusion gene drives human chronic myeloid leukemia (CML). The last 2 decades have witnessed that specific tyrosine kinase inhibitors (TKIs, e.g., imatinib mesylate, IM) against ABL1 improve disease treatment, although some patients still suffer from relapse and TKI resistance. Therefore, a better understanding of the molecular pathology of CML is still urgently needed. miR-181a-5p (miR-181a) acts as a tumor suppressor in CML; however, the molecular mechanism of miR-181a in CML stem/progenitor cells remains elusive. Herein, we showed that miR-181a inhibited the growth of CML CD34+ cells, including the quiescent subset, and sensitized them to IM treatment, while miR-181a inhibition by a sponge sequence collaborated with BCR-ABL to enhance the growth of normal CD34+ cells. Transcriptome data and biochemical analysis revealed that SERPINE1 was a bona fide and critical target of miR-181a, which deepened the understanding of the regulatory mechanism of SERPINE1. Genetic and pharmacological inhibition of SERPINE1 led to apoptosis mainly mediated by caspase-9 activation. The dual inhibition of SERPINE1 and BCR-ABL exhibited a significantly stronger inhibitory effect than a single agent. Taken together, this study demonstrates that a novel miR-181a/SERPINE1 axis modulates CML stem/progenitor cells, which likely provides an important approach to override TKI resistance.

Trans-anal Minimally Invasive Surgery Combined With a Robotic Anterior Approach for Sleeve Resection of a Huge Rectal Gastrointestinal Stromal Tumor.

Due to anatomical complexity, large rectal gastrointestinal stromal tumors (GISTs) in the pelvis at the anterior aspect often require extended abdominal surgery to obtain clear surgical margins. Here, we show our trans-anal minimally invasive surgery combined with a robotic anterior approach for a huge low rectal GIST that was widely in contact with the prostate and urethra. By performing lateral dissection first, we can identify the orientation of critical organs such as the prostate, urethra, and neurovascular bundles, facilitating anterior anorectal dissection without urethral injury. Although the combination with a transabdominal robotic approach was required because of firm inflammatory adhesion between the tumor and prostate, the preceding trans-anal dissection plane facilitated the robotic anterior dissection and contributed to achieving complete dissection with negative resection margins.

A conserved ZFX/WNT3 axis modulates the growth and imatinib response of chronic myeloid leukemia stem/progenitor cells.

BACKGROUND: Zinc finger protein X-linked (ZFX) has been shown to promote the growth of tumor cells, including leukemic cells. However, the role of ZFX in the growth and drug response of chronic myeloid leukemia (CML) stem/progenitor cells remains unclear. METHODS: Real-time quantitative PCR (RT-qPCR) and immunofluorescence were used to analyze the expression of ZFX and WNT3 in CML CD34+ cells compared with normal control cells. Short hairpin RNAs (shRNAs) and clustered regularly interspaced short palindromic repeats/dead CRISPR-associated protein 9 (CRISPR/dCas9) technologies were used to study the role of ZFX in growth and drug response of CML cells. Microarray data were generated to compare ZFX-silenced CML CD34+ cells with their controls. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to study the molecular mechanisms of ZFX to regulate WNT3 expression. RT-qPCR and western blotting were used to study the effect of ZFX on ß-catenin signaling. RESULTS: We showed that ZFX expression was significantly higher in CML CD34+ cells than in control cells. Overexpression and gene silencing experiments indicated that ZFX promoted the in vitro growth of CML cells, conferred imatinib mesylate (IM) resistance to these cells, and enhanced BCR/ABL-induced malignant transformation. Microarray data and subsequent validation revealed that WNT3 transcription was conservatively regulated by ZFX. WNT3 was highly expressed in CML CD34+ cells, and WNT3 regulated the growth and IM response of these cells similarly to ZFX. Moreover, WNT3 overexpression partially rescued ZFX silencing-induced growth inhibition and IM hypersensitivity. ZFX silencing decreased WNT3/ß-catenin signaling, including c-MYC and CCND1 expression. CONCLUSION: The present study identified a novel ZFX/WNT3 axis that modulates the growth and IM response of CML stem/progenitor cells.

Ripretinib for the treatment of advanced, imatinib-resistant gastrointestinal stromal tumors.

Discovery of constitutive activation of KIT/PDGFRA tyrosine kinases in gastrointestinal stromal tumors (GISTs) leads to the development of the targeted drug imatinib. However, the inevitable development of imatinib resistance remains a major issue. Ripretinib is a novel targeted drug that inhibits the activities of a broad spectrum of drug-resistant KIT/PDGFRA mutants. It was approved in 2020 and is currently recommended by major international guidelines as the fourth-line and beyond therapy for advanced GISTs. Emerging evidence shows that ripretinib is superior to sunitinib as a second-line treatment for KIT exon 11-mutated GISTs due to its activity against highly heterogeneous frequently occurring secondary mutations. This review summarizes current data on the use of ripretinib to treat advanced imatinib-resistant GISTs. We also propose future research directions to improve the targeted GIST treatment.

Injectable Gamboge-Based In Situ Gel for Sustained Delivery of Imatinib Mesylate.

The aim of this study was to prepare and characterize the imatinib mesylate (IM)-loaded gamboge-based ISG system for local administration of an anticancer agent against colorectal carcinoma. The ISG formulations were prepared in dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP). The physicochemical properties, drug release profile, and cytotoxicity of the developed formulations were assessed. The developed ISG demonstrated Newtonian flow behavior with acceptable rheological and mechanical properties. The viscosity of the developed ISG, measured at less than 80 cP, and the applied forces of less than 50 N·mm, indicated easy administration using clinical injection techniques. Upon contact with an aqueous phase, the ISG immediately formed a porous cross-sectional structure, enabling sustained release of IM over 14 days. The release profile of IM was fitted to the quasi-Fickian diffusion mechanism, and the release rate could be controlled by the types of solvent and the amount of IM content. The developed IM-loaded gamboge ISG effectively inhibited colorectal cancer cells, including HCT116 and HT29 cell lines, with less than 20% cell viability observed at a concentration of 1% w/w IM after 2 days of incubation. This suggests that the developed ISG may potentially serve as an injectable system for localized anticancer delivery against colorectal cells, potentially reducing the side effects of systemic chemotherapy and improving patient adherence.

Analysis of potential Circular RNAs in regulating imatinib resistance of Gastrointestinal stromal tumor.

INTRODUCTION: Recent studies have found that circular RNA is an abundant RNA species that belongs to part of the competing endogenous RNA network(ceRNA), which was proven to play an important role in the development, diagnosis and progress of diseases. However, the function of circRNAs in imatinib resistance in Gastrointestinal stromal tumor (GIST) are poorly understood so for. The present study aimed to screen and predict the potential circRNAs in imatinib resistance of GIST using microarray analysis. METHODS: We determined the expression of circular RNAs in paired normal gastric tissues(N), primary GIST (gastrointestinal stromal tumor) tissues (YC) and imatinib mesylate secondary resistance GIST tissues(C) with microarray and predicted 8677 dysregulated circular RNAs. RESULTS: Compared with the YC group, we identified 15 circRNAs that were up-regulated and 8 circRNAs that were down-regulated in the C group. Gene ontology (GO)and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that these host linear transcripts that differentially express circular RNAs are involved in many key biological pathways, predicting the potential tumor-genesis and drug resistance mechanismrelated to HIF-1 pathway, later we draw the cirRNA-miRNA-mRNA network involved in the HIF-1 pathway and found several dysregulated circRNAs and the relationship between circRNA-miRNAs-mRNA, such as circRNA_06551, circRNA_14668, circRNA_04497, circRNA_08683, circRNA_09923(Green, down-regulation) and circRNA_23636, circRNA_15734(Red, up-regulation). CONCLUSION: Taken together, we identified a panel of dysregulated circRNAs that may be potential biomarkers even therapy relevant to the GIST, especially imatinib secondary resistance GIST.