Scientific Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.
Curr Treat Options Oncol. 2024 Nov;25(11):1390-1405. doi: 10.1007/s11864-024-01272-7. Epub 2024 Oct 23.
Gastrointestinal stromal tumor (GIST) is characterized by well-defined oncogenes. Despite the significant improvement in treatment outcomes with adjuvant imatinib therapy for patients, drug resistance remains a major challenge for GIST therapy. This review focuses on the mechanisms contributing to drug resistance phenotype in GIST, such as primary imatinib-resistant mutants, secondary mutations, non-covalent binding of TKI to its target, tumor heterogeneity, re-activation of pro-survival/proliferation pathways through non-KIT/PDGFRA kinases, and loss of therapeutic targets in wild-type GIST. Corresponding suggestions are proposed to overcome drug-resistance phenotype of GIST. This review also summarizes the suitability of currently approved TKIs on different KIT/PDGFRA mutations and updates related clinical trials. Recent potent drugs and emerging strategies against advanced GISTs in clinical trials are presented. Additionally, metabolic intervention offers a new avenue for clinical management in GIST. A landscape of metabolism in GIST and metabolic changes under imatinib treatment are summarized based on currently published data. The OXPHOS pathway is a promising therapeutic target in combination with TKI against sensitive KIT/PDGFRA mutants. Comprehensive understanding of the above resistance mechanisms, experimental drugs/strategies and metabolic changes is critical to implement the proper therapy strategy and improve the clinical therapy outcomes for GIST.
胃肠道间质瘤（GIST）的特征是明确的致癌基因。尽管辅助伊马替尼治疗患者的治疗效果显著改善，但药物耐药仍然是 GIST 治疗的主要挑战。本综述重点介绍了导致 GIST 药物耐药表型的机制，如原发性伊马替尼耐药突变体、继发性突变、TKI 与靶标的非共价结合、肿瘤异质性、通过非 KIT/PDGFRA 激酶重新激活生存/增殖途径，以及野生型 GIST 中治疗靶点的丧失。针对 GIST 的药物耐药表型提出了相应的建议。本文还总结了目前批准的 TKI 在不同的 KIT/PDGFRA 突变中的适用性，并更新了相关的临床试验。介绍了临床试验中针对晚期 GIST 的最近有效的药物和新兴策略。此外，代谢干预为 GIST 的临床管理提供了新途径。根据目前已发表的数据，总结了 GIST 中的代谢以及伊马替尼治疗下的代谢变化。氧化磷酸化（OXPHOS）途径是一种有前途的治疗靶点，可与针对敏感 KIT/PDGFRA 突变体的 TKI 联合使用。全面了解上述耐药机制、实验药物/策略和代谢变化，对于实施适当的治疗策略和改善 GIST 的临床治疗效果至关重要。
