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.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract and originate from the interstitial cells of Cajal (ICC), which is the pacemaker for peristaltic movement in the gastrointestinal tract. Existing GIST cell lines are widely used as cell models for in vitro experimental studies because the mutation sites are known. However, the immortalization methods of these cell lines are unknown, and no Chinese patient-derived GIST cell lines have been documented. Here, we transfected simian virus 40 large T antigen (SV40LT) into primary GIST cells to establish an immortalized human GIST cell line (ImGIST) for the first time. The ImGIST cells had neuronal cell-like irregular radioactive growth and retained the fusion growth characteristics of GIST cells. They stably expressed signature proteins, maintained the biological and genomic characteristics of normal primary GIST cells, and responded well to imatinib, suggesting that ImGIST could be a potential in vitro model for research in GIST to explore the molecular pathogenesis, drug resistance mechanisms, and the development of new adjuvant therapeutic options.

Background: With the advances in gastrointestinal stromal tumors (GISTs) research and the development of new immunotherapy drugs, the emergence of targeted drugs has greatly changed the diagnosis and treatment of GISTs and benefited more GIST patients. However, drug resistance has become increasingly challenging with the widespread application of targeted therapy in GIST patients. Based on the currently available evidence, the United States Food and Drug Administration (US FDA) has approved sunitinib as a second-line therapy and regorafenib as a third-line therapy, and research and development of more molecularly-targeted drugs are underway. Case Description: A middle-aged male patient was diagnosed with advanced small intestine GIST. Following the resection (R2) of tumors in the small intestine and pelvis, the patient received first-, second-, and third-line adjuvant therapies. However, follow-up examinations indicated progressive disease (PD). Ripretinib was then administered as the fourth-line therapy, and partial response (PR) was achieved 6 months later. To the best of our knowledge, this is a rare case in which the fourth-line adjuvant therapy for GIST achieved significant efficacy after unsuccessful systematic first-, second-, and third-line therapies. Conclusions: Imatinib, as the first-choice targeted therapy for advanced GISTs, has achieved notable clinical efficacy. After localized tumor progression on imatinib, second-line sunitinib may be applied. Third-line regorafenib therapy can be used in patients with GISTs who have failed both imatinib and sunitinib. In our current case, the patient experienced PD after regorafenib administration, and a satisfactory efficacy was obtained following the use of ripretinib. For patients with GISTs, after the failure of imatinib, sunitinib, and regorafenib, ripretinib may achieve a good therapeutic effect as a new targeted drug. Ripretinib is currently approved for use as a fourth-line or higher therapy in advanced GISTs, However, the ultimate place of ripretinib in metastatic or advanced GIST remains under investigation. This case achieved the therapeutic effect of PR through the treatment of repatinib, and there were no other obvious side effects except hair loss. Our findings may inform clinical decision-making regarding the treatment of GISTs. Keywords: Gastrointestinal stromal tumor (GIST); imatinib; ripretinib; case report

Background: Gastric cancer (GC) ranks as the fifth most prevalent malignancy and the third leading cause of cancer-related mortality worldwide, with complex pathogenesis driven by genetic and epigenetic alterations. While genetic contributors to GC have been extensively studied, the functional role of N6-methyladenosine (m6A) RNA methylation—the most abundant eukaryotic RNA modification—in gastric carcinogenesis remains insufficiently characterized. This study aimed to investigate transcriptome-wide m6A methylation dysregulation and its mechanistic implications in GC progression. Methods: Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was performed to map m6A epitranscriptomes in paired GC and adjacent normal tissues. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted on 253 hypomethylated mRNAs to delineate the biological pathways associated with m6A dysregulation. The transcriptomic profiles were analyzed using RNA-seq, while a retrospective cohort analysis (n = 58) evaluated the correlations between IGF2BP3 expression and the clinicopathological characteristics of patients with GC. Results: MeRIP-seq analysis demonstrated transcriptome-wide m6A hypomethylation in GC tissues, identifying 271 significantly reduced peaks (p < 0.01). Functional annotation revealed enrichment of hypomethylated transcripts in metabolic pathways and transcriptional dysregulation. Notably, m6A-related genes exhibited widespread activation in GC, with IGF2BP3 showing the most pronounced upregulation (106-fold increase, p < 0.0001). Clinically, elevated IGF2BP3 expression significantly correlated with lymph node involvement (p = 0.016) and advanced TNM staging (p = 0.028). Conclusion: This study establishes m6A methylation dysregulation as a critical mechanism in GC pathogenesis and identifies IGF2BP3 as both a potential therapeutic target and a prognostic biomarker in GC.