Imatinib In Gastrointestinal Stromal Tumors Research Articles

Characteristics and predictors of outcomes with neoadjuvant imatinib in gastrointestinal stromal tumors: Real-world data from a large patient registry.

737 Background: The standard of care for patients with moderate or high-risk resectable gastrointestinal stromal tumors (GIST) is surgical resection followed by adjuvant therapy with imatinib. The impact of neoadjuvant imatinib on long-term outcomes is largely unknown. Methods: We interrogated the LifeRaft registry, a large international open cohort of patients with GIST. We included patients who did not have metastatic disease at diagnosis, underwent surgical resection and received neoadjuvant imatinib and had no recorded mutations of Kit exon 13 or PDGFRA exon 18 D842V. Baseline patient characteristics were described and survival probabilities were estimated and plotted using the Kaplan-Meier method. Cox regression was used to estimate the effect of demographic and clinical characteristics on recurrence-free survival (RFS) and overall survival (OS). For RFS, time was calculated from the date of surgery to disease recurrence/death, whichever came first. For OS, time was calculated from the date of surgery to death. Estimated effects of predictors were reported as hazard ratios (HR) along with 95% confidence intervals (CI). All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Results: Out 2,472 patients with GIST, 137 patients met the inclusion criteria and received neoadjuvant imatinib for a median of 6.8 months. Majority of the patients were aged 40 years or above (129/137, 94.2%) and were males (73/137, 53.3%). The majority of the patients had gastric GIST (72/137, 54.1%), followed by small intestine GIST (34/137, 25.6%) and other (27/137, 20.3%). Most patients had a tumor size of >10 cm (66/137, 52.4%) at the time of diagnosis followed by >5 cm - <=10 cm (42/137, 33.3%) and >2 cm - <=5 cm (18/137, 14.3%). The median RFS for the cohort was 6.1 years. On multivariable analysis, tumor size (HR 1.08, 95% CI 1.05-1.12, p<0.01) and the overall duration of treatment (neoadjuvant and adjuvant) with imatinib therapy (HR 0.98, 95% CI 0.97-0.99, p<0.01) were significantly associated with RFS. A 1-cm increase in tumor size and 1-month increase in total time on imatinib was associated with an 8% increase and 2% decrease in risk of recurrence. The median OS was 14.2 years. Female gender (HR 0.23 95% CI 0.08-0.65, p<0.01) and total length of time on imatinib (HR 0.97 95% CI 0.96-0.99, p<0.01) were found to be significantly associated with OS. Female patients were associated with a 77% decreased risk of death and a 1-month increase in the total time on imatinib was associated with a 3% decrease in the risk of death. Conclusions: We show that most patients receiving neoadjuvant imatinib have gastric GIST with tumor size >10 cm. Smaller tumor size and female gender predicted longer RFS and OS respectively. Longer total duration of imatinib therapy was associated with increased RFS and OS.

FBXW7 regulates the sensitivity of imatinib in gastrointestinal stromal tumors by targeting MCL1.

Imatinib contributes to improving prognosis of high-risk or unresectable gastrointestinal stromal tumors (GISTs). As therapeutic efficacy is limited by imatinib resistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that enables patients to utilize more effective therapeutic strategies remains urgent. The correlation between FBXW7 and imatinib resistance via FBXW7-MCL1 axis was evaluated in vitro and in vivo experiments. The significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs. The ability of FBXW7 to predict therapeutic efficacy of adjuvant imatinib in high-risk GIST patients was determined through 5-year recurrence-free survival (RFS) rates analysis and multivariate analysis. FBXW7 affects imatinib sensitivity by regulating apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate apoptosis. MCL1 involves in the regulation of imatinib sensitivity through inhibiting apoptosis in GIST-T1 cells. FBXW7 regulates imatinib sensitivity by down-regulating MCL1 to enhance imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells by targeting MCL1 to predict efficacy of imatinib treatment in vivo. FBXW7 regulates imatinib sensitivity by inhibiting MCL1 to enhance imatinib-induced apoptosis in GIST, and predicts efficacy of imatinib treatment in high-risk GIST patients treated with imatinib.

Adjuvant Targeted Therapy in Solid Cancers: Pioneers and New Glories.

Targeted therapy (TT) has revolutionized cancer treatment, successfully applied in various settings. Adjuvant TT in resected early-stage gastrointestinal stromal tumors (GIST), melanoma, non-small cell lung cancer (NSCLC), and breast cancer has led to practice-changing achievements. In particular, standard treatments include BRAF inhibitors for melanoma, osimertinib for NSCLC, hormone therapy or HER2 TT for breast cancer, and imatinib for GIST. Despite the undeniable benefit derived from adjuvant TT, the optimal duration of TT and the appropriate managing of the relapse remain open questions. Furthermore, neoadjuvant TT is emerging as valuable, particularly in breast cancer, and ongoing studies evaluate TT in the perioperative setting for early-stage NSCLC. In this review, we aim to collect and describe the large amount of data available in the literature about adjuvant TT across different histologies, focusing on epidemiology, major advances, and future directions.

A mutation-based radiomics signature predicts response to imatinib in Gastrointestinal Stromal Tumors (GIST)

ObjectivesTo develop a mutation-based radiomics signature to predict response to imatinib in Gastrointestinal Stromal Tumors (GISTs). MethodsEighty-two patients with GIST were enrolled in this retrospective study, including 52 patients from one center that were used to develop the model, and 30 patients from a second center to validate it. Reference standard was the mutational status of tyrosine-protein kinase (KIT) and platelet-derived growth factor α (PDGFRA). Patients were dichotomized in imatinib sensitive (group 0 - mutation in KIT or PDGFRA, different from exon 18-D842V), and imatinib non-responsive (group 1 - PDGFRA exon 18-D842V mutation or absence of mutation in KIT/PDGFRA). Initially, 107 texture features were extracted from the tumor masks of baseline computed tomography scans. Different machine learning methods were then implemented to select the best combination of features for the development of the radiomics signature. ResultsThe best performance was obtained with the 5 features selected by the ANOVA model and the Bayes classifier, using a threshold of 0.36. With this setting the radiomics signature had an accuracy and precision for sensitive patients of 82 % (95 % CI:60–95) and 90 % (95 % CI:73–97), respectively. Conversely, a precision of 80 % (95 % CI:34–97) was obtained in non-responsive patients using a threshold of 0.9. Indeed, with the latter setting 4 patients out of 5 were correctly predicted as non-responders. ConclusionsThe results are a first step towards using radiomics to improve the management of patients with GIST, especially when tumor tissue is unavailable for molecular analysis or when molecular profiling is inconclusive.

Advances in the research of the mechanism of secondary resistance to imatinib in gastrointestinal stromal tumors.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. At present, surgery is the first-line treatment for primary resectable GISTs; however, the recurrence rate is high. Imatinib mesylate (IM) is an effective first-line drug used for the treatment of unresectable or metastatic recurrent GISTs. More than 80% of patients with GISTs show significantly improved 5-year survival after treatment; however, approximately 50% of patients develop drug resistance after 2 years of IM treatment. Therefore, an in-depth research is urgently needed to reveal the mechanisms of secondary resistance to IM in patients with GISTs and to develop new therapeutic targets and regimens to improve their long-term prognoses. In this review, research on the mechanisms of secondary resistance to IM conducted in the last 5 years is discussed and summarized from the aspects of abnormal energy metabolism, gene mutations, non-coding RNA, and key proteins. Studies have shown that different drug-resistance mechanism networks are closely linked and interconnected. However, the influence of these drug-resistance mechanisms has not been compared. The combined inhibition of drug-resistance mechanisms with IM therapy and the combined inhibition of multiple drug-resistance mechanisms are expected to become new therapeutic options in the treatment of GISTs. In addition, implementing individualized therapies based on the identification of resistance mechanisms will provide new adjuvant treatment options for patients with IM-resistant GISTs, thereby delaying the progression of GISTs. Previous studies provide theoretical support for solving the problems of drug-resistance mechanisms. However, most studies on drug-resistance mechanisms are still in the research stage. Further clinical studies are needed to confirm the safety and efficacy of the inhibition of drug-resistance mechanisms as a potential therapeutic target.

Circ-CCS enhances autophagy during imatinib resistance of gastrointestinal stromal tumor by regulating miR-197-3p/ATG10 signaling.

Drug resistance in gastrointestinal stromal tumors (GISTs) is connected with autophagy activation. Accumulating data demonstrates the critical role of circular RNAs (circRNAs) dysregulation in this development. To explore the possible function of hsa_circ_0092306 (circ-CCS) in GIST imatinib resistance. Quantitative real-time reverse transcription PCR (RT-qPCR) was used to determine the expression levels of circ-CCS and miR-197-3p. The vitality and apoptosis of cells were determined using the Cell Counting Kit-8 and TUNEL assays, respectively. Western blot analysis was used to evaluate the relative protein expression. A dual-luciferase reporter assay was used to validate the link between circ-CCS, miR-197-3p, and ATG10. Comparisons of two groups were analyzed using Student's t tests, and analysis of variance (ANOVA) with Tukey's post hoc test was used to compare three or more groups. Circulating-CCS expression was considerably increased in the serum of imatinib-resistant GIST patients (P < 0.001). Circulating-CCS deficiency decreased cell proliferation and autophagy in GIST-882 and GIST-T1 cells, but promoted apoptosis (P < 0.05). Additionally, circ-CCS was predominantly found in the cytoplasm. Mechanically, circ-CCS targeted miR-197-3p, which may influence autophagy by downregulating ATG10, in order to modulate GIST cells' malignant tendencies. Moreover, silencing miR-197-3p reversed the effect of circ-CCS knockdown on apoptosis and autophagy in GIST cells. By modulating the miR-197-3p/ATG10 axis, circ-CCS increased imatinib resistance in GIST cells, establishing a potential target for reversing medication resistance in such patients.

BRD9 inhibition promotes PUMA-dependent apoptosis and augments the effect of imatinib in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GISTs) are primarily characterized by activating mutations of tyrosine kinase or platelet-derived growth factor receptor alpha. Although the revolutionary therapeutic outcomes of imatinib are well known, the long-term benefits of imatinib are still unclear. The effects of BRD9, a recently identified subunit of noncanonical BAF complex (ncBAF) chromatin remodeling complexes, in GISTs are not clear. In the current study, we evaluated the functional role of BRD9 in GIST progression. Our findings demonstrated that the expression of BRD9 was upregulated in GIST tissues. The downregulation or inhibition of BRD9 could significantly reduce cellular proliferation, and facilitates apoptosis in GISTs. BRD9 inhibition could promote PUMA-dependent apoptosis in GISTs and enhance imatinib activity in vitro and in vivo. BRD9 inhibition synergizes with imatinib in GISTs by inducing PUMA upregulation. Mechanism study revealed that BRD9 inhibition promotes PUMA induction via the TUFT1/AKT/GSK-3β/p65 axis. Furthermore, imatinib also upregulates PUMA by targeting AKT/GSK-3β/p65 axis. In conclusion, our results indicated that BRD9 plays a key role in the progression of GISTs. Inhibition of BRD9 is a novel therapeutic strategy in GISTs treated alone or in combination with imatinib.

Type and Gene Location of KIT Mutations Predict Progression-Free Survival to First-Line Imatinib in Gastrointestinal Stromal Tumors: A Look into the Exon.

Simple SummaryAlthough effective in the majority of patients, the progression-free survival (PFS) to imatinib treatment can vary widely in effectiveness. Based on the known predictive role of tyrosine kinase (KIT) and platelet-derived growth factor receptor α (PDGRA) tumor genotypes, the differential clinical response to first-line imatinib treatment might be related to the different types and gene locations of the mutations. In our study, metastatic patients with gastrointestinal stromal tumors (GIST)-carrying KIT exon 11 deletion or a deletion/insertion involving codons 557/558 showed significantly shorter PFS to imatinib compared with those with deletion in codons other than 557/558 and patients with exon 11 duplication, insertion or single nucleotide variants (SNVs). Conversely, the latter subgroup showed the longest PFS first-line to imatinib. These results highlight the predictive role of pathogenic variant (PV) type and codon location in GIST, and can support stratification via mutational status in future clinical trials.In previous studies on localized GISTs, KIT exon 11 deletions and mutations involving codons 557/558 showed an adverse prognostic influence on recurrence-free survival. In the metastatic setting, there are limited data on how mutation type and codon location might contribute to progression-free survival (PFS) variability to first-line imatinib treatment. We analyzed the type and gene location of KIT and PDGFRA mutations for 206 patients from a GIST System database prospectively collected at an Italian reference center between January 2005 and September 2020. By describing the mutational landscape, we focused on clinicopathological characteristics according to the critical mutations and investigated the predictive role of type and gene location of the KIT exon 11 mutations in metastatic patients treated with first-line imatinib. Our data showed a predictive impact of KIT exon 11 pathogenic variant on PFS to imatinib treatment: patients with deletion or insertion/deletion (delins) in 557/558 codons had a shorter PFS (median PFS: 24 months) compared to the patients with a deletion in other codons, or duplication/insertion/SNV (median PFS: 43 and 49 months, respectively) (p < 0.001). These results reached an independent value in the multivariate model, which showed that the absence of exon 11 deletions or delins 557/558, the female gender, primitive tumor diameter (≤5 cm) and polymorphonuclear leucocytosis (>7.5 109/L) were significant prognostic factors for longer PFS. Analysis of the predictive role of PDGFRA PVs showed no significant results. Our results also confirm the aggressive biology of 557/558 deletions/delins in the metastatic setting and allow for prediction at the baseline which GIST patients would develop resistance to first-line imatinib treatment earlier.

18F-FDG PET/CT in GIST treatment response evaluation beyond Imatinib.

Positron emission tomography/computed tomography (PET/CT) represents a reliable promising tool in treatment response evaluation of new therapies beyond Imatinib in gastrointestinal stromal tumors (GIST). This narrative review aims to discuss the literature about the role of fluorine-18-fluorodeoxyglucose (18F-FDG) PET/CT in evaluating response in new tyrosine kinase inhibitors (TKI) and radiotherapy (RT) in GIST patients. A comprehensive literature search was performed to retrieve original studies published on PubMed, Scopus and Google Scholar databases. Eighteen studies including 382 patients with GIST were selected. Main findings of included studies are presented. Fluorine-18-FDG PET/CT may enhance performance in GIST management providing significant information in evaluation of treatment response and representing a strong predictor of clinical outcome.

Treatment of gastrointestinal tumor (GIST) of the rectum requiring abdominoperineal resection following neoadjuvant imatinib: a cost-effectiveness analysis

BackgroundNeoadjuvant imatinib for gastrointestinal stromal tumors (GIST) of the rectum can reduce, but may not eliminate, risk of surgical morbidity from permanent bowel diversion. We sought to evaluate the cost-effectiveness of alternative strategies in rectal GIST patients requiring abdominoperineal resection following neoadjuvant imatinib.MethodsWe developed a Markov model using a healthcare payers’ perspective to estimate costs in 2017 Singapore dollars (SGD) and quality adjusted life years (QALYs) for upfront abdominoperineal resection (UAPR) versus continued imatinib until progression (CIUP) following 1 year of neoadjuvant imatinib. Transition probabilities and utilities were obtained from published data, and costs were estimated using data from the National Cancer Centre Singapore. Deterministic and probabilistic sensitivity analyses were conducted to probe model uncertainty. Incremental cost-effectiveness ratio below SGD 50,000 per QALY gained was considered cost-effective.ResultsIn the base case, UAPR dominates CIUP being both more effective (8.66 QALYS vs 5.43 QALYs) and less expensive (SGD 312,627 vs SGD 339,011). These estimates were most sensitive to 2 variables, utility of abdominoperineal resection and annual recurrence probability post-abdominoperineal resection. However, simultaneously varying the values of these variables to maximally favor CIUP did not render it the more cost effective strategy at willingness to pay (WTP) of SGD 50,000. In probabilistic sensitivity analysis, UAPR had probability of being cost-effective compared with CIUP greater than 95%, reaching 100% at WTP SGD 10,000.ConclusionUAPR is more effective and less costly than CIUP for patients with rectal GIST requiring abdominoperineal resection following neoadjuvant imatinib, and is the strategy of choice in this setting.

P-305 Efficacy and safety of IMATINIB in gastrointestinal stromal tumors: Experience of the medical oncology department of the CHU Hassan II of Fez

Gastrointestinal Stromal Tumors (GIST) are a very rare form of cancers of the digestive tract belonging to the sarcoma family. They are characterized by an overexpression of C-kit in immunohistochemistry and by activating mutations of tyrosine kinase receptors. Targeted therapies against these receptors such as IMATINIB and then SUNITINIB have transformed the management and prognosis of advanced and metastatic forms. The aim of this work was to study the efficacy and tolerance of IMATINIB in gastrointestinal stromal tumors. A retrospective study was carried out in the medical oncology department of the Hassan II University Hospital in Fez, collecting 67 patients with a gastrointestinal stromal tumor during the period from April 2013 to April 2019. The statistical analysis of the results was done by SPSS version 23 software, the survival was calculated by the Kaplan-Meier method. The average age of the patients was 59 years with a clear male predominance (sex ratio of 1.5). The most frequent localization was gastric in 33 cases, followed by the small intestine in 21 cases, then other localizations in 13 cases. The most common symptom was pain, reported in 85% of cases. Surgery was the means of diagnostic confirmation in 76% of the cases. At the end of the radiological and histological assessment, the diagnosis of localized GIST was retained in 38 cases, locally advanced in 11 cases and metastatic in 18 cases. Surgery was performed in 46 patients. All patients received treatment with IMATINIB. The most common side effects were: * Asthenia: observed in 30% of patients. * Hematotoxicity: 15% thrombocytopenia, 20% anemia and 10% leukopenia. * Cutaneous-mucous: 47% of hand-foot syndrome, 25% of mucositis, 15% of skin rash and depigmentation of the hair was observed in 5% of patients. * Digestive: vomiting and nausea occurred in 20% of patients. 35% of patients developed edema of the lower limbs and 25% of periorbital edema. 20% of patients developed dysthyroidism and hypertension was observed in 10% of patients. After a median follow-up of 23 months, all the patients were alive and the median progression-free survival was 7 months. The safety profile of IMATINIB used in our study was comparable to the global tolerance reported in the literature. More studies are needed to investigate the relationship between their toxicity and their efficacy in the Moroccan population.

1704P - Neo-adjuvant (NA) Imatinib for gastrointestinal stromal tumours (GISTs): What is the optimal length of treatment?

BackgroundGISTs are rare tumours with an incidence of around 1/100000/year. The principle treatment in localised disease remains resection. If an R0 resection is not expected, Imatinib can be used in the NA setting to shrink tumours and improve chances of a complete resection. Current guidelines suggest Imatinib should be used for 6-12 months in the NA setting. MethodsData were collected for patients treated for GISTs with Imatinib in either the NA or palliative (PA) setting in two UK tertiary centres to assess response in the primary tumour volume (PTV). This study aimed to find the time to maximum reduction of PTV in NA and PA settings. Results29 patients were treated with Imatinib over a 3 year period; 13 in the PA setting and 16 in the NA setting. In the NA setting, 10 patients proceeded to surgery, 2 patients declined surgery and 4 patients remained inoperable. All patients deemed operable at baseline underwent surgery after NA Imatinib. The median time to surgery was 7.2mths (Range (R) 1.6 – 28.9mths). Overall, 10 patients died (none in the NA setting), 5 on treatment and 5 post-treatment. At baseline, the median PTV was 199.3cm3 (R 4.0 – 10472.0cm3). The median time to best response was 7.6mths (R 1.4 – 46.2mths) for all patients, 4.7mths (R 1.4 – 21.6mths) in NA patients and 14.1mths (R 3.3 – 46.2mths) in PA patients. As the majority of NA patients did not have progressive disease (PD) prior to surgery, the maximum response may not have been reached and therefore the results in PA patients may better reflect the time to best response. 9 patients had PD, 2 in NA setting with 1 patient proceeding to surgery. The median time to PD for all patients was 19.6mths (R 1 – 51.4mts). The overall response rate to Imatinib was 85.2%. The median reduction in PTV was 65.3% (R -182.7 – 93.4%). In NA patients the median reduction in PTV was 62.7% (R -182.7 – 93.4%) and in PA patients the median reduction in PTV was 57.6% (R 20 – 82.4%). ConclusionsImatinib has high response rates in both the NA and PA settings. This study suggests the maximum reduction in PTV can be achieved after greater than 12mths of treatment. For patients responding to NA Imatinib who have ongoing concerns regarding resectability, a more prolonged course of treatment may further reduce PTV to facilitate an R0 resection. Legal entity responsible for the studySharath Gangadhara. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Type I Interferon Signaling Contributes to Antitumor Immune Response and is Reduced by Imatinib in Gastrointestinal Stromal Tumor (GIST)

Type I Interferon Signaling Contributes to Antitumor Immune Response and is Reduced by Imatinib in Gastrointestinal Stromal Tumor (GIST)

Research advances in the secondary resistance mechanism of imatinib in gastrointestinal stromal tumors

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumors in the gastrointestinal tract. Though surgical resection is the only radical treatment, postoperative recurrence and metastasis often occur. The first-line therapy for the treatment of recurrent, metastatic and unresectable GIST is imatinib. More than 80% of patients can benefit from imatinib treatment, but half of patients will still have recurrence or metastasis within 2 years after treatment initiation, and secondary drug resistance is a major cause of disease progression. Therefore, adeep understanding of the mechanisms of secondary drug resistance will guide us to develop personalized therapeutic schedule in the future. This article describes the mechanism of IM secondary resistance from the aspects of gene alteration, abnormal activation of signal transduction pathway, autophagy, apoptosis and drug concentration. It is found that single drug therapy has certain limitations in patients with secondary resistance to IM. Using IM combined with downstream signaling molecule inhibitors, autophagy inhibitors, insulin-like growth factor 1 receptor (IGF-1R) inhibitors, heat shock protein 90 (HSP90) inhibitors, cytotoxic T lymphocyte - associated antigen - 4 (CTLA - 4) antibodies and mitochondrial inhibitors provide us new therapeutic ideas. However, these combination treatments are still in the research phase, and further trials are needed to confirm the safety and efficacy. With the gradual deepening of research on drug resistance mechanisms, it will provide more solutions to the current serious drug resistance problem.

Adjuvant therapy with imatinib in gastrointestinal stromal tumors (GISTs)-review and perspectives.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal (GI) tract. Most of them (>75%) are driven by an oncogenic initiating event involving activating mutations of the genes encoding for tyrosine kinase, KIT or platelet derived growth factor receptor alpha (PDGFRA). Efficacy of the tyrosine kinase Inhibitor imatinib is now well established for advanced disease. For localized GISTs, 3 years treatment is the recommended adjuvant therapy for high risk patients. Whether a longer duration and selection of patients for this adjuvant therapy in localized GISTs remains is not yet established (PERSIST-5 study). Similarly, it will be important to further refine the definition of the population of GIST patients at high risk of relapse including molecular criteria (Annals of Oncology, ESMO guidelines 2018). This review aims to describe current knowledges on the issue of adjuvant therapy of primary GISTs in view of available results.

Downregulation of lncRNA CCDC26 contributes to imatinib resistance in human gastrointestinal stromal tumors through IGF-1R upregulation.

Imatinib is the first line of therapy for patients with metastatic or gastrointestinal stromal tumors (GIST). However, drug resistance limits the long-term effect of imatinib. Long non-coding RNAs (lncRNAs) are emerging as key players in regulating drug resistance in cancer. In this study, we investigated the association between lncRNA CCDC26 and IGF-1R in GIST and their involvement in drug resistance. Considering the key role of lncRNAs in drug resistance in cancer, we hypothesized that IGF-1R is regulated by lncRNAs. The expression of a series of reported drug resistance-related lncRNAs, including CCDC26, ARF, H19, NBR2, NEAT1, and HOTAIR, in GIST cells treated with imatinib H19 was examined at various time-points by qRT-PCR. Based on our results and published literature, CCDC26, a strongly down-regulated lncRNA following imatinib treatment, was chosen as our research target. GIST cells with high expression of CCDC26 were sensitive to imatinib treatment while knockdown of CCDC26 significantly increased the resistance to imatinib. Furthermore, we found that CCDC26 interacted with c-KIT by RNA pull down, and that CCDC26 knockdown up-regulated the expression of IGF-1R. Moreover, IGF-1R inhibition reversed CCDC26 knockdown-mediated imatinib resistance in GIST. These results indicated that treatments targeting CCDC26-IGF-1R axis would be useful in increasing sensitivity to imatinib in GIST.

Mechanisms of the resistance of gastrointestinal stromal tumors to imatinib

The review describes the modern concepts of the primary and secondary (acquired) resistance of gastrointestinal stromal tumors to the targeted drug imatinib. Gastrointestinal stromal tumors are the mesenchymal tumors of gastrointestinal tract that originate from interstitial cells of Cajal or their stem cell precursors. Up to 85 % of gastrointestinal stromal tumors have the mutations of KIT gene that lead to ligand-independent activation of this tyrosine kinase. Imatinib is an inhibitor of KIT tyrosine kinase which is hyperexpressed in 70-85 % of cases on the cell membrane of gastrointestinal stromal tumors. Despite the high effectiveness of imatinib in gastrointestinal stromal tumors, up to 15 % of patients do not respond to this therapy, and over 50 % of patients acquire the resistance to this drug 2 years after initiation of target therapy with imatinib. The mechanisms of primary resistance include basically the mutational status of KIT, PDGFRA and, rarely, mutations of SDH, NF1, BRAF, PI3K3CA, CBL, and KRAS. The mechanisms of secondary resistance of tumor cells to imatinib are not restricted to the secondary mutations of KIT and PDGFRA, but also might be due to the loss of KIT expression associated by overexpression of the alternative receptor- and non-receptor tyrosine kinases, such as MET, AXL, FGFR2α, FAK, etc. Alternative mechanisms of acquired resistance might be due to the mutations of BRAF gene.

A Novel Receptor Tyrosine Kinase Switch Promotes Gastrointestinal Stromal Tumor Drug Resistance.

The fact that most gastrointestinal stromal tumors (GISTs) acquire resistance to imatinib (IM)-based targeted therapy remains the main driving force to identify novel molecular targets that are capable to increase GISTs sensitivity to the current therapeutic regimens. Secondary resistance to IM in GISTs typically occurs due to several mechanisms that include hemi- or homo-zygous deletion of the wild-type KIT allele, overexpression of focal adhesion kinase (FAK) and insulin-like growth factor receptor I (IGF-1R) amplification, BRAF mutation, a RTK switch (loss of c-KIT and gain of c-MET/AXL), etc. We established and characterized the IM-resistant GIST T-1 cell line (GIST T-1R) lacking secondary c-KIT mutations typical for the IM-resistant phenotype. The resistance to IM in GIST T-1R cells was due to RTK switch (loss of c-KIT/gain of FGFR2α). Indeed, we have found that FGFR inhibition reduced cellular viability, induced apoptosis and affected the growth kinetics of the IM-resistant GISTs in vitro. In contrast, IM-naive GIST T-1 parental cells were not susceptible to FGFR inhibition. Importantly, inhibition of FGF-signaling restored the susceptibility to IM in IM-resistant GISTs. Additionally, IM-resistant GISTs were less susceptible to certain chemotherapeutic agents as compared to parental IM-sensitive GIST cells. The chemoresistance in GIST T-1R cells is not due to overexpression of ABC-related transporter proteins and might be the result of upregulation of DNA damage signaling and repair (DDR) genes involved in DNA double-strand break (DSB) repair pathways (e.g., XRCC3, Rad51, etc.). Taken together, the established GIST T-1R cell subline might be used for in vitro and in vivo studies to examine the efficacy and prospective use of FGFR inhibitors for patients with IM-resistant, un-resectable and metastatic forms of GISTs with the type of RTK switch indicated above.

Imatinib and hypophosphatemia: Case report and review of literature

Abstract Imatinib mesylate is a potent inhibitor of the BCR-Abl kinases, c-Kit, PDGFR, and fms. Imatinib used for treatment of chronic myeloid leukemia and gastrointestinal stromal tumor. Imatinib has been well tolerated. The most common adverse events reported included edema, nausea, diarrhea, myalgia or musculoskeletal pain, fatigue, dermatitis or rash, headache and abdominal pain. Hypophosphatemia is rare side effect of imatinib treatment. This is the report of a case experiencing severe hypophosphatemia during adjuvant treatment with imatinib for gastrointestinal stromal tumor.

PIK3C2A is a gene-specific target of microRNA-518a-5p in imatinib mesylate-resistant gastrointestinal stromal tumor

Imatinib mesylate resistance occurs in some patients with gastrointestinal stromal tumors (GISTs) during the course of treatment. In this study, we investigated the relationship between microRNAs (miRNAs) and imatinib-resistant GISTs, and the effect of miR-518a-5p on PIK3C2A in imatinib-resistant GISTs. A total of 20 matched-pair GIST samples from imatinib-resistant patients were included in the study. Each of the paired tumor specimens were from the same patient who had surgical removal of GISTs preimatinib and postimatinib treatment. Seven pairs of tissues were resected for microarray analysis, and the remaining 13 pairs were utilized for miRNAs analysis. Target genes were selected based on bioinformatics from multiple biological databases. Luciferase reporter assays were used to confirm the binding of miR-518a-5p to PIK3C2A 3′UTR. GIST882R-NC, 882R-miR-518a-5p-OE, and 882R-miR-518a-5p-KD cell lines were constructed using lentiviral vectors. miR-518a-5p and PIK3C2A expression in 882R-NC, 882R-OE, and 882R-KD cells was assessed by real-time PCR and western blotting. A cell counting kit was used to detect the influence of miR-518a-5p to cell proliferation. TUNEL staining was applied to detect the influence of miR-518a-5p to cell apoptosis. Microarray analysis showed that miR-518a-5p was downregulated in imatinib-resistant GISTs, and the expression of miR-518a-5p was confirmed with good concordance between real-time PCR and miRNA microarray results. Luciferase reporter assays indicated that miR-518a-5p bound to the PIK3C2A 3′UTR. Compared with 882R-OE, PIK3C2A expression was significantly increased in 882R-KD cells. MiR-518a-5p reduced 882R proliferation and promoted 882R apoptosis. In conclusion, PIK3C2A is a gene-specific target of miR-518a-5p in imatinib mesylate-resistant GISTs. Low expression of miR-518a-5p is likely to upregulate PIK3C2A and affect the cellular response to the drug, causing resistance to imatinib in GISTs.