Article
Medicine, General & Internal
Jean-Yves Blay, Yoon-Koo Kang, Toshiroo Nishida, Margaret von Mehren
Summary: Gastrointestinal stromal tumours (GIST) are rare malignancies with 80% of cases having KIT or PDGFRA activating mutations. Localized GIST can be cured through surgery, while advanced resistant GIST with resistance mutations require treatment with new drugs.
NATURE REVIEWS DISEASE PRIMERS
(2021)
Article
Oncology
Shujing Li, Sien Zhao, Nianhai Liang, Shaoting Zhang, Liangying Zhang, Liangji Zhou, Anbu Liu, Xu Cao, Jinhai Tian, Yuanyuan Yu, Zhaoyang Fan, Kun Xiao, Ming Wang, Hui Zhao, Ru Bai, Jianmin Sun
Summary: In this study, the researchers investigated the role of SPRY4 in GISTs and its related mechanisms. They found that SPRY4 inhibits the expression and activation of KIT in GISTs, leading to decreased cell survival and proliferation. Additionally, SPRY4 enhances the inhibitory effect of Imatinib on primary KIT mutants, but has no effect on drug-resistant secondary KIT mutants.
Article
Biochemistry & Molecular Biology
Takuma Hayashi, Ikuo Konishi
Summary: Through cancer genome testing, a germline pathogenic variant of the KIT gene was detected in a 32-year-old male patient with advanced GISTs, confirming the diagnosis of familial multinodular GIST. Treatment with imatinib resulted in long-term regression of GISTs in this patient. Therefore, cancer genome testing can be used to diagnose malignant tumors and select new therapeutic agents for advanced malignancies.
Article
Oncology
Luna De Sutter, Agnieszka Wozniak, Jasper Verreet, Ulla Vanleeuw, Lore De Cock, Nina Linde, Christine Drechsler, Christina Esdar, Raf Sciot, Patrick Schoffski
Summary: In this study, the efficacy of a novel selective KIT inhibitor, IDRX-42, was tested in 4 GIST xenograft models. The results showed that IDRX-42 could cause tumor volume reduction, decrease mitotic activity, and induce myxoid degeneration in models with KIT exon 13 mutation. These findings indicate that IDRX-42 has significant antitumor activity in GIST.
CLINICAL CANCER RESEARCH
(2023)
Article
Oncology
Juan Liu, Jingjing Gao, Aoli Wang, Zongru Jiang, Shuang Qi, Ziping Qi, Feiyang Liu, Kailin Yu, Jiangyan Cao, Cheng Chen, Chen Hu, Hong Wu, Li Wang, Wenchao Wang, Qingsong Liu, Jing Liu
Summary: Drug resistance is a major challenge in the treatment of gastrointestinal stromal tumours (GISTs). A study has found that nintedanib can overcome resistance caused by mutations in the KIT gene and upregulation of fibroblast growth factor (FGF) activity. Nintedanib also showed inhibitory effects on cell proliferation and ERK phosphorylation in preclinical GIST models.
MOLECULAR ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Anbu Liu, Shaoting Zhang, Ming Wang, Liangying Zhang, Shidong Xu, Ahmad Nasimian, Shujing Li, Sien Zhao, Xu Cao, Jinhai Tian, Yuanyuan Yu, Zhaoyang Fan, Kun Xiao, Hui Zhao, Julhash U. Kazi, Lijun Ma, Jianmin Sun
Summary: This study demonstrates that DDR1/2 contribute to KIT activation and enhance resistance to imatinib in GISTs, providing a rationale for further exploration of DDR1/2 targeting in GIST treatment.
MOLECULAR CARCINOGENESIS
(2023)
Article
Oncology
Lorena Incorvaia, Daniele Fanale, Bruno Vincenzi, Ida De Luca, Tommaso Vincenzo Bartolotta, Roberto Cannella, Gianni Pantuso, Daniela Cabibi, Antonio Russo, Viviana Bazan, Giuseppe Badalamenti
Summary: The study suggests that the PFS of GIST patients to imatinib treatment may be related to different mutation types and locations of the KIT exon 11 gene, which have predictive value. Patients with deletions or insertions/deletions in codons 557/558 showed shorter PFS, while those with other types of mutations exhibited longer PFS.
Review
Oncology
Lillian R. Klug, Homma M. Khosroyani, Jason D. Kent, Michael C. Heinrich
Summary: When Gastrointestinal Stromal Tumour (GIST) was identified as a distinct pathological entity, effective medical therapies were lacking, leading to poor prognosis. However, the discovery of KIT mutations and the development of TKIs revolutionized GIST treatment. Although there are approved drugs for treating advanced-stage GIST, challenges still remain and new therapeutic approaches are needed.
NATURE REVIEWS CLINICAL ONCOLOGY
(2022)
Article
Medicine, Research & Experimental
Shuai Ye, Dinara Sharipova, Marya Kozinova, Lilli Klug, Jimson D'Souza, Martin G. Belinsky, Katherine J. Johnson, Margret B. Einarson, Karthik Devarajan, Yan Zhou, Samuel Litwin, Michael C. Heinrich, Ronald DeMatteo, Margaret von Mehren, James S. Duncan, Lori Rink
Summary: The management of Gastrointestinal Stromal Tumors (GISTs) has been greatly influenced by the identification of activating mutations in KIT and PDGFRA and the clinical application of RTK inhibitors. Despite the effectiveness of these inhibitors in most cases, resistance remains a clinical challenge, necessitating the identification of novel targets for refractory GISTs. Global kinome profiling shows promise in uncovering critical signaling networks and essential protein kinases in GISTs.
Review
Oncology
Bayan Al-Share, Abdulrahman Alloghbi, Mohammed Najeeb Al Hallak, Hafiz Uddin, Asfar Azmi, Ramzi M. Mohammad, Steve H. Kim, Anthony F. Shields, Philip A. Philip
Summary: GIST is a rare tumor originating from the interstitial cells of Cajal in the gastrointestinal tract, with surgery being the only curative treatment for localized disease. Targeted therapies like imatinib have shown improved survival rates in patients. FDA-approved new tyrosine kinase inhibitors, avapritinib and ripretinib, provide options for heavily pretreated advanced GIST. Future shifts in therapy paradigms are likely to occur in the treatment of GIST.
CANCER AND METASTASIS REVIEWS
(2021)
Article
Biochemistry & Molecular Biology
Wangzhen He, Liangliang Xu, Jiongyan Ding, Li Song, Weili Yang, Isabella Klooster, Daniel F. Pilco-Janeta, Cesar Serrano, Hongming Fang, Guojun Jiang, Xiaoyan Wang, Jiren Yu, Wen-Bin Ou
Summary: Most GISTs have mutations in the receptor tyrosine kinase KIT/PDGFRA, which provides a potential target for therapy. However, these tumors often develop resistance to the KIT/PDGFRA inhibitor imatinib. This study found that the non-RTK activated kinase ACK1 is overexpressed in GISTs. Inhibition of ACK1 using a specific inhibitor or siRNA suppressed cell viability and migration, and also inhibited signaling pathways and epithelial-mesenchymal transition. Co-targeting ACK1 and KIT showed additive effects in suppressing proliferation and promoting apoptosis, as well as inhibiting invasiveness and migration in GIST cells.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Article
Biochemistry & Molecular Biology
Hyunho Yoon, Chih-Min Tang, Sudeep Banerjee, Mayra Yebra, Sangkyu Noh, Adam M. Burgoyne, Jorge De la Torre, Martina De Siena, Mengyuan Liu, Lillian R. Klug, Yoon Young Choi, Mojgan Hosseini, Antonio L. Delgado, Zhiyong Wang, Randall P. French, Andrew Lowy, Ronald P. DeMatteo, Michael C. Heinrich, Alfredo A. Molinolo, J. Silvio Gutkind, Olivier Harismendy, Jason K. Sicklick
Summary: This study identified a paracrine signaling network in the tumor microenvironment where cancer-associated fibroblasts drive GIST growth and metastasis through the production of PDGFC. Targeting CAFs with a dual PI3K/mTOR inhibitor synergized with imatinib to increase tumor cell killing. This new cellular target for GIST therapy may improve disease control and cure rates.
Review
Oncology
Cesar Serrano, Javier Martin-Broto, Jose Manuel Asencio-Pascual, Jose Antonio Lopez-Guerrero, Jordi Rubio-Casadevall, Silvia Bague, Xavier Garcia-del-Muro, Juan angel Fernandez-Hernandez, Luis Herrero, Antonio Lopez-Pousa, Andres Poveda, Virginia Martinez-Marin, GEIS Grp Espanol Invest en Sarcomas, Spanish Grp Sarcoma Res
Summary: Gastrointestinal stromal tumor (GIST) is a common malignant tumor of mesenchymal origin with a wide clinical spectrum. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, and targeted tyrosine kinase inhibitors have significantly improved outcomes in the treatment of this previously chemoresistant cancer. This review provides evidence-based guidelines for the management of GIST, developed by a multidisciplinary expert panel, and offers a standard approach for diagnosis, treatment, and follow-up.
THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
(2023)
Review
Pharmacology & Pharmacy
Simon Fung, Matt Shirley
Summary: Ripretinib is a small molecule inhibitor that targets a wide range of mutations in gastrointestinal stromal tumors, leading to an increase in progression-free survival. It has acceptable tolerability and is a valuable treatment option for managing this disease.
Article
Oncology
Matthew L. Hemming, Morgan R. Benson, Michael A. Loycano, Justin A. Anderson, Jessica L. Andersen, Madeleine L. Taddei, Andrei Krivtsov, Brandon J. Aubrey, Jevon A. Cutler, Charlie Hatton, Ewa Sicinska, Scott A. Armstrong
Summary: Gastrointestinal stromal tumor (GIST) relies on epigenetic regulation of KIT and other essential genes. Through genome-scale CRISPR dependency screens, chromatin-modifying complexes MOZ and Menin-MLL were found to be crucial in GIST and disrupting these complexes could be a potential therapeutic approach.