Gastrointestinal mesenchymal stromal tumor (GIST) is a relatively rare disease that has leapt from a tumor that was difficult to eradicate with surgery and had a poor prognosis with insensitive radiotherapy to a benchmark for targeted tumor therapy that has attracted the attention of oncology researchers worldwide because of the clear molecular mechanism of pathogenesis and the development of novel drugs that have achieved incredible efficacy. A review of GIST’s decades of development reveals that GIST’s continuous therapeutic advances and increasingly better efficacy have followed the great progress made in modern molecular genetics of tumors, and is a representative disease that has gained breakthrough progress due to the development of modern medicine and is a pioneer of individualized medicine. GIST was not the “star” of tumor research once it was discovered. As early as 1960, Matin et al. first reported a cytoplasm-rich round or polygonal cell tumor from the gastric wall, named gastric epithelioid smooth muscle tumor. In 1962, Stout named this mesenchymal tumor of the stomach, “chimeric smooth muscle tumor” or “smooth muscle cell tumor”; in 1969, it was called epithelioid smooth muscle cell tumor in the WHO tumor classification, because no evidence of smooth muscle was found on electron microscopy, so tumor researchers seemed to pay no attention to GIST. In 1983, Mazur and Clark found that most gastrointestinal mesenchymal tumors lacked the characteristics of smooth muscle cells, and thus introduced the concept of gastrointestinal mesenchymal tumor, which was defined as a gastrointestinal spindle cell tumor of unknown biological behavior and origin. tumors of unknown biological behavior and origin. Since then, the concept of gastrointestinal mesenchymal tumor (GIST) has become more recognized and accepted by most people. However, while research on other high-incidence tumors was in full swing, there was still very little research on this disease, which was not sensitive to radiotherapy and had a poor prognosis, and GIST was once again forgotten. Time came in 1998 when Kindblon et al. showed that GIST was similar to Cajal cells around the intermuscular plexus of the gastrointestinal tract, both positive for c-kit gene, CD117, and CD34 expression. In the same year, Seiichi Hirota et al. from Osaka University School of Medicine in Japan reported that GIST contained activated c-KIT mutations and also found that this functionally acquired mutation plays a key role in the pathogenesis of GIST. Since then, GIST research has been on a fast track, and in the last decade or so, its achievements have rapidly surpassed those of other solid tumors that have taken decades of research, making it a worthy target for other tumor research. The success of the molecularly targeted drug Imatinib and the breakthroughs in the treatment of GIST have revolutionized the treatment strategy of GIST. Talking about Imatinib, we have to mention another disease, chronic granulocytic leukemia. In the 1980s, scientists discovered that this leukemia is mainly due to the uncontrolled and continuous signal of the BCR/ABL fusion protein that allows the cells to proliferate, which is the cause of the tumor. Could this uncontrolled kinase be turned off? Brian Druker, then a 29-year-old physician, came up with the idea of killing tumor cells by rationally designing a drug to shut off the active site of this kinase and inhibit the expression of this enzyme. Through collaboration with scientists at Novartis, a drug was screened – code name STI571 – that effectively killed chronic granulocytic leukemia cancer cells in vitro, those containing the Philadelphia chromosome disappeared, and had no effect on normal cells, showing that this drug had good promise for treating chronic granulocytic leukemia. However, the pharmaceutical company had little interest in the drug because the incidence of chronic granulocytic leukemia is about 1 in 100,000, with only about 70,000 patients worldwide, and the development of the drug required a huge investment that could barely be recouped with so few patients. druker finally decided to conduct clinical trials through lengthy communication and arguments with the company, and later, due to the amazing results shown by the drug The FDA approved it for marketing in 2001 without conducting a Phase III clinical trial, and the drug codenamed STI571 was later known as Gleevec. The first was Heikki Joensuu, a medical oncologist from Finland, who met a 50-year-old female patient, later known as Patient Zero, who had a 4-year history of metastatic GIST. The patient had undergone multiple surgeries and systemic chemotherapy with adriamycin and cyclophosphamide, but the tumor continued to grow and there was no other treatment available at that time. Meanwhile, two other scientists, Jonathan Fletcher and Dr. George Demetri from Harvard Medical School, had discovered in the laboratory that Gleevec could inhibit not only the BCR/ABL fusion protein but also the expression of the c-KIT mutation in GIST, but there was no clinical data confirming the drug’s effectiveness in GIST. After full consultation with the patient, Joensuu decided to give Gleevec, and after treatment imaging showed significant tumor shrinkage and a significant decrease in FDG?PET metabolic activity. Biopsies before and after treatment showed largely liquefied and necrotic masses, and a report of the treatment of this case was published in the October 2001 issue of the New England Journal of Medicine. Thereafter, the efficacy of Gleevec in GIST was confirmed when Drs. Demetri and Joensuu rapidly initiated a clinical trial of imatinib in GIST in the U.S. and Europe, and the FDA approved Gleevec for the treatment of gastrointestinal mesenchymal tumors in 2002, a rare indication in the history of the FDA to use Phase II clinical trial data to approve the use of a drug. The success of Gleevec saved the lives of patients, brought great honor to the developers, and was also lucrative for the company. Subsequently, in 2003, Dr. Fletcher discovered another gene mutation in GIST – PDGFRA mutation. c-KIT mutation and PDGFRA mutation can constitute about 86% of GIST, and Fletcher’s lab subsequently published a series of important research results on GIST, which established the GIST The Fletcher lab subsequently published a series of important findings on GIST, which established the status of the world’s number one laboratory for GIST research. However, scientists found that, similar to other tumors, a group of patients previously treated with Gleevec eventually develop resistance, meaning they are no longer sensitive to Gleevec. Tumor cells are always working against humans, and when there is a drug that blocks the cell growth signal generated by the primary mutation, the tumor cells always keep finding ways to escape, and finally they managed to find a way – the creation of a secondary mutation, which led to the failure of GIST to imatinib treatment. Fortunately, human beings who are fighting against tumors are also smart enough, Dr. Demetri again verified that for patients who are resistant to imatinib, a second drug, sunitinib, can be used with good results, and the research results were published in The Lancet in 2006, and in the same year, the FDA approved sunitinib as a second-line treatment for GIST, however, for some sites of secondary mutations, sunitinib treatment is not effective, and drug resistance still occurs after sunitinib treatment. Dr. Demetri led another team study to identify a third effective drug, regorafenib, which significantly prolongs survival in patients resistant to imatinib and sunitinib treatment, and the FDA approved regorafenib as a third-line treatment for GIST in 2013. The progress of GIST research cannot be separated from the exploration of scientists such as Seiichi Hirota and Jonathan Fletcher in the laboratory, clinicians such as Brian Druker, Heikki Joensuu, George Demetri and others who overcame many difficulties to conduct clinical trials, and Patient Zero The selfless dedication of these GIST patients participated in these studies, which benefited subsequent GIST patients. They have left a deep footprint in the history of tumor research. At present, molecular biology research of GIST has entered a more mature stage, and molecular genetic information has deeply penetrated into the topics of etiology, pathogenesis, diagnosis, targeted therapy, drug resistance mechanism and prognosis judgment, thus the treatment effect of GIST has changed dramatically. At present, the global treatment of GIST basically refers to the clinical practice guidelines published by the National Comprehensive Cancer Network (NCCN). The translator is fortunate to be engaged in GIST research under the guidance of Fletcher and Demetri, and is interested in GIST research, so he has excerpted and translated the GIST content of the NCCN clinical practice guidelines for sarcoma into Chinese for the convenience of clinicians. We would also like to invite readers’ criticism and correction to facilitate the update of corrections in the coming year.