PDF herunterladen
CC BY 4.0 · Glob Med Genet 2024; 11(04): 251-262
DOI: 10.1055/s-0044-1789204
Review Article

Gene Mutations in Gastrointestinal Stromal Tumors: Advances in Treatment and Mechanism Research

Lei Cao   *
1   Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
2   Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, People's Republic of China
,
Wencong Tian   *
1   Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
,
Yongjie Zhao
1   Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
2   Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, People's Republic of China
,
Peng Song
1   Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
,
Jia Zhao
1   Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
,
Chuntao Wang
1   Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
,
Yanhong Liu
1   Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
,
Hong Fang
1   Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
,
Xingqiang Liu
1   Department of General Surgery, Tianjin Union Medical Center, Tianjin, People's Republic of China
› Institutsangaben Funding This work was supported by the Tianjin Medical Key Discipline (Specialty) Construction Project (TJYXZDXK-058B) and the Tianjin Health Research Project (TJWJ2023XK014).
› Weitere Informationen
Auch verfügbar auf
   Lizenzen und Reprints

Abstract

Although gastrointestinal stromal tumors (GISTs) has been reported in patients of all ages, its diagnosis is more common in elders. The two most common types of mutation, receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor a (PDGFRA) mutations, hold about 75 and 15% of GISTs cases, respectively. Tumors without KIT or PDGFRA mutations are known as wild type (WT)-GISTs, which takes up for 15% of all cases. WT-GISTs have other genetic alterations, including mutations of the succinate dehydrogenase and serine–threonine protein kinase BRAF and neurofibromatosis type 1. Other GISTs without any of the above genetic mutations are named “quadruple WT” GISTs. More types of rare mutations are being reported. These mutations or gene fusions were initially thought to be mutually exclusive in primary GISTs, but recently it has been reported that some of these rare mutations coexist with KIT or PDGFRA mutations. The treatment and management differ according to molecular subtypes of GISTs. Especially for patients with late-stage tumors, developing a personalized chemotherapy regimen based on mutation status is of great help to improve patient survival and quality of life. At present, imatinib mesylate is an effective first-line drug for the treatment of unresectable or metastatic recurrent GISTs, but how to overcome drug resistance is still an important clinical problem. The effectiveness of other drugs is being further evaluated. The progress in the study of relevant mechanisms also provides the possibility to develop new targets or new drugs.

Keywords

GISTs - gene mutation - molecular mechanism - targeted therapies - drug resistance

* Lei Cao and Wencong Tian contributed equally to this work.




Publikationsverlauf

Artikel online veröffentlicht:
22. August 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Nannini M, Astolfi A, Urbini M. et al. Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST). BMC Cancer 2014; 14: 685
    CrossrefPubMedGoogle Scholar
  • 2 Arima J, Hiramatsu M, Taniguchi K. et al. Multiple gastrointestinal stromal tumors caused by a novel germline KIT gene mutation (Asp820Gly): a case report and literature review. Gastric Cancer 2020; 23 (04) 760-764
    CrossrefPubMedGoogle Scholar
  • 3 Zhou S, Abdihamid O, Tan F. et al. KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST. Cell Commun Signal 2024; 22 (01) 153
    CrossrefPubMedGoogle Scholar
  • 4 Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998; 152 (05) 1259-1269
    PubMedGoogle Scholar
  • 5 Li J, Ye Y, Wang J. et al; Chinese Society Of Clinical Oncology Csco Expert Committee On Gastrointestinal Stromal Tumor. Chinese consensus guidelines for diagnosis and management of gastrointestinal stromal tumor. Chin J Cancer Res 2017; 29 (04) 281-293
    CrossrefPubMedGoogle Scholar
  • 6 Napolitano A, Thway K, Smith MJ, Huang PH, Jones RL. KIT exon 9-mutated gastrointestinal stromal tumours: biology and treatment. Chemotherapy 2022; 67 (02) 81-90
    CrossrefPubMedGoogle Scholar
  • 7 Blay JY, Kang YK, Nishida T, von Mehren M. Gastrointestinal stromal tumours. Nat Rev Dis Primers 2021; 7 (01) 22
    CrossrefPubMedGoogle Scholar
  • 8 Casali PG, Abecassis N, Aro HT. et al; ESMO Guidelines Committee and EURACAN. Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; 29 (Suppl. 04) iv267
    CrossrefPubMedGoogle Scholar
  • 9 Boikos SA, Pappo AS, Killian JK. et al. Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2016; 2 (07) 922-928
    CrossrefPubMedGoogle Scholar
  • 10 Sawaki A. Rare gastrointestinal stromal tumors (GIST): omentum and retroperitoneum. Transl Gastroenterol Hepatol 2017; 2: 116
    CrossrefPubMedGoogle Scholar
  • 11 Verschoor AJ, Bovée JVMG, Overbeek LIH, Hogendoorn PCW, Gelderblom H. PALGA group. The incidence, mutational status, risk classification and referral pattern of gastro-intestinal stromal tumours in the Netherlands: a nationwide pathology registry (PALGA) study. Virchows Arch 2018; 472 (02) 221-229
    CrossrefPubMedGoogle Scholar
  • 12 Ma GL, Murphy JD, Martinez ME, Sicklick JK. Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study. Cancer Epidemiol Biomarkers Prev 2015; 24 (01) 298-302
    CrossrefPubMedGoogle Scholar
  • 13 Miettinen M, Lasota J. Gastrointestinal stromal tumors. Gastroenterol Clin North Am 2013; 42 (02) 399-415
    CrossrefPubMedGoogle Scholar
  • 14 Nishida T, Goto O, Raut CP, Yahagi N. Diagnostic and treatment strategy for small gastrointestinal stromal tumors. Cancer 2016; 122 (20) 3110-3118
    CrossrefPubMedGoogle Scholar
  • 15 Schaefer IM, Mariño-Enríquez A, Fletcher JA. What is new in gastrointestinal stromal tumor?. Adv Anat Pathol 2017; 24 (05) 259-267
    CrossrefPubMedGoogle Scholar
  • 16 Nishida T, Blay JY, Hirota S, Kitagawa Y, Kang YK. The standard diagnosis, treatment, and follow-up of gastrointestinal stromal tumors based on guidelines. Gastric Cancer 2016; 19 (01) 3-14
    CrossrefPubMedGoogle Scholar
  • 17 Lai S, Wang G, Cao X. et al. KIT over-expression by p55PIK-PI3K leads to imatinib-resistance in patients with gastrointestinal stromal tumors. Oncotarget 2016; 7 (02) 1367-1379
    CrossrefPubMedGoogle Scholar
  • 18 Pantaleo MA, Nannini M, Corless CL, Heinrich MC. Quadruple wild-type (WT) GIST: defining the subset of GIST that lacks abnormalities of KIT, PDGFRA, SDH, or RAS signaling pathways. Cancer Med 2015; 4 (01) 101-103
    CrossrefPubMedGoogle Scholar
  • 19 Søreide K, Sandvik OM, Søreide JA, Giljaca V, Jureckova A, Bulusu VR. Global epidemiology of gastrointestinal stromal tumours (GIST): a systematic review of population-based cohort studies. Cancer Epidemiol 2016; 40: 39-46
    CrossrefPubMedGoogle Scholar
  • 20 Joensuu H, Hohenberger P, Corless CL. Gastrointestinal stromal tumour. Lancet 2013; 382 (9896) 973-983
    CrossrefPubMedGoogle Scholar
  • 21 Nannini M, Biasco G, Astolfi A, Pantaleo MA. An overview on molecular biology of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST). J Med Genet 2013; 50 (10) 653-661
    CrossrefPubMedGoogle Scholar
  • 22 Machado I, Claramunt-Alonso R, Lavernia J. et al. ETV6:NTRK3 fusion-positive wild-type gastrointestinal stromal tumor (GIST) with abundant lymphoid infiltration (TILs and tertiary lymphoid structures): a report on a new case with therapeutic implications and a literature review. Int J Mol Sci 2024; 25 (07) 3707
    CrossrefPubMedGoogle Scholar
  • 23 Shi E, Chmielecki J, Tang CM. et al. FGFR1 and NTRK3 actionable alterations in “wild-type” gastrointestinal stromal tumors. J Transl Med 2016; 14 (01) 339
    CrossrefPubMedGoogle Scholar
  • 24 Wu J, Zhou H, Yi X. et al. Targeted deep sequencing reveals unrecognized KIT mutation coexistent with NF1 deficiency in GISTs. Cancer Manag Res 2021; 13: 297-306
    CrossrefPubMedGoogle Scholar
  • 25 Gheorghe G, Bacalbasa N, Ceobanu G. et al. Gastrointestinal stromal tumors-a mini review. J Pers Med 2021; 11 (08) 694
    CrossrefPubMedGoogle Scholar
  • 26 Pathania S, Pentikäinen OT, Singh PK. A holistic view on c-Kit in cancer: structure, signaling, pathophysiology and its inhibitors. Biochim Biophys Acta Rev Cancer 2021; 1876 (02) 188631
    CrossrefPubMedGoogle Scholar
  • 27 Szucs Z, Thway K, Fisher C. et al. Molecular subtypes of gastrointestinal stromal tumors and their prognostic and therapeutic implications. Future Oncol 2017; 13 (01) 93-107
    CrossrefPubMedGoogle Scholar
  • 28 Smrke A, Gennatas S, Huang P, Jones RL. Avapritinib in the treatment of PDGFRA exon 18 mutated gastrointestinal stromal tumors. Future Oncol 2020; 16 (22) 1639-1646
    CrossrefPubMedGoogle Scholar
  • 29 Joensuu H, Rutkowski P, Nishida T. et al. KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence. J Clin Oncol 2015; 33 (06) 634-642
    CrossrefPubMedGoogle Scholar
  • 30 Calderillo-Ruíz G, Pérez-Yepez EA, García-Gámez MA. et al. Genomic profiling in GIST: implications in clinical outcome and future challenges. Neoplasia 2024; 48: 100959
    CrossrefPubMedGoogle Scholar
  • 31 Brčić I, Argyropoulos A, Liegl-Atzwanger B. Update on molecular genetics of gastrointestinal stromal tumors. Diagnostics (Basel) 2021; 11 (02) 194
    CrossrefPubMedGoogle Scholar
  • 32 Wozniak A, Rutkowski P, Schöffski P. et al. Tumor genotype is an independent prognostic factor in primary gastrointestinal stromal tumors of gastric origin: a European multicenter analysis based on ConticaGIST. Clin Cancer Res 2014; 20 (23) 6105-6116
    CrossrefPubMedGoogle Scholar
  • 33 Casali PG, Abecassis N, Aro HT. et al; ESMO Guidelines Committee and EURACAN. Soft tissue and visceral sarcomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; 29 (Suppl. 04) iv268-iv269
    CrossrefPubMedGoogle Scholar
  • 34 Künstlinger H, Huss S, Merkelbach-Bruse S. et al. Gastrointestinal stromal tumors with KIT exon 9 mutations: update on genotype-phenotype correlation and validation of a high-resolution melting assay for mutational testing. Am J Surg Pathol 2013; 37 (11) 1648-1659
    CrossrefPubMedGoogle Scholar
  • 35 Zeng S, Seifert AM, Zhang JQ. et al. Wnt/β-catenin signaling contributes to tumor malignancy and is targetable in gastrointestinal stromal tumor. Mol Cancer Ther 2017; 16 (09) 1954-1966
    CrossrefPubMedGoogle Scholar
  • 36 Niinuma T, Suzuki H, Sugai T. Molecular characterization and pathogenesis of gastrointestinal stromal tumor. Transl Gastroenterol Hepatol 2018; 3: 2
    CrossrefPubMedGoogle Scholar
  • 37 Ito T, Yamamura M, Hirai T. et al. Gastrointestinal stromal tumors with exon 8 c-kit gene mutation might occur at extragastric sites and have metastasis-prone nature. Int J Clin Exp Pathol 2014; 7 (11) 8024-8031
    PubMedGoogle Scholar
  • 38 George S, Blay JY, Casali PG. et al Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur. J. Cancer 2009; 45: 1959-1968
    CrossrefPubMedGoogle Scholar
  • 39 Corless CL, Schroeder A, Griffith D. et al Heinrich M.C. PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J. Clin. Oncol 2005; 23: 5357-5364
    CrossrefPubMedGoogle Scholar
  • 40 Masucci MT, Motti ML, Minopoli M, Di Carluccio G, Carriero MV. Emerging targeted therapeutic strategies to overcome imatinib resistance of gastrointestinal stromal tumors. Int J Mol Sci 2023; 24 (07) 6026
    CrossrefPubMedGoogle Scholar
  • 41 Pharaon N, Habbal W, Monem F. Bioinformatic analysis of KIT juxtamembrane domain mutations in Syrian GIST patients: jigsaw puzzle completed. J Egypt Natl Canc Inst 2023; 35 (01) 25
    CrossrefPubMedGoogle Scholar
  • 42 Shi X, Sousa LP, Mandel-Bausch EM. et al. Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition. Proc Natl Acad Sci U S A 2016; 113 (33) E4784-E4793
    PubMedGoogle Scholar
  • 43 Reshetnyak AV, Opatowsky Y, Boggon TJ. et al. The strength and cooperativity of KIT ectodomain contacts determine normal ligand-dependent stimulation or oncogenic activation in cancer. Mol Cell 2015; 57 (01) 191-201
    CrossrefPubMedGoogle Scholar
  • 44 Obata Y, Horikawa K, Takahashi T. et al. Oncogenic signaling by Kit tyrosine kinase occurs selectively on the Golgi apparatus in gastrointestinal stromal tumors. Oncogene 2017; 36 (26) 3661-3672
    CrossrefPubMedGoogle Scholar
  • 45 Obata Y, Kurokawa K, Tojima T. et al. Golgi retention and oncogenic KIT signaling via PLCγ2-PKD2-PI4KIIIβ activation in gastrointestinal stromal tumor cells. Cell Rep 2023; 42 (09) 113035
    CrossrefPubMedGoogle Scholar
  • 46 Tsai M, Valent P, Galli SJ. KIT as a master regulator of the mast cell lineage. J Allergy Clin Immunol 2022; 149 (06) 1845-1854
    CrossrefPubMedGoogle Scholar
  • 47 Masson K, Heiss E, Band H, Rönnstrand L. Direct binding of Cbl to Tyr568 and Tyr936 of the stem cell factor receptor/c-Kit is required for ligand-induced ubiquitination, internalization and degradation. Biochem J 2006; 399 (01) 59-67
    CrossrefPubMedGoogle Scholar
  • 48 Lennartsson J, Rönnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev 2012; 92 (04) 1619-1649
    CrossrefPubMedGoogle Scholar
  • 49 Zhao R, Song Y, Wang Y. et al. PD-1/PD-L1 blockade rescue exhausted CD8+ T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway. Cell Prolif 2019; 52 (03) e12571
    CrossrefPubMedGoogle Scholar
  • 50 Bosbach B, Rossi F, Yozgat Y. et al. Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor. Proc Natl Acad Sci U S A 2017; 114 (40) E8448-E8457
    CrossrefPubMedGoogle Scholar
  • 51 Blay JY, Shen L, Kang YK. et al. Nilotinib versus imatinib as first-line therapy for patients with unresectable or metastatic gastrointestinal stromal tumours (ENESTg1): a randomised phase 3 trial. Lancet Oncol 2015; 16 (05) 550-560
    CrossrefPubMedGoogle Scholar
  • 52 Gastrointestinal Stromal Tumor Meta-Analysis G, Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol 2010; 28 (07) 1247-1253
    CrossrefPubMedGoogle Scholar
  • 53 Blanke CD, Demetri GD, von Mehren M. et al. Long-term results from a randomized phase II trial of standard- versus higher-dose imatinib mesylate for patients with unresectable or metastatic gastrointestinal stromal tumors expressing KIT. J Clin Oncol 2008; 26 (04) 620-625
    CrossrefPubMedGoogle Scholar
  • 54 Blanke CD, Rankin C, Demetri GD. et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol 2008; 26 (04) 626-632
    CrossrefPubMedGoogle Scholar
  • 55 Cassier PA, Fumagalli E, Rutkowski P. et al; European Organisation for Research and Treatment of Cancer. Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. Clin Cancer Res 2012; 18 (16) 4458-4464
    CrossrefPubMedGoogle Scholar
  • 56 Debiec-Rychter M, Sciot R, Le Cesne A. et al; EORTC Soft Tissue and Bone Sarcoma Group, Italian Sarcoma Group, Australasian GastroIntestinal Trials Group. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 2006; 42 (08) 1093-1103
    CrossrefPubMedGoogle Scholar
  • 57 Heinrich MC, Corless CL, Blanke CD. et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 2006; 24 (29) 4764-4774
    CrossrefPubMedGoogle Scholar
  • 58 Patrikidou A, Domont J, Chabaud S. et al; French Sarcoma Group. Long-term outcome of molecular subgroups of GIST patients treated with standard-dose imatinib in the BFR14 trial of the French Sarcoma Group. Eur J Cancer 2016; 52: 173-180
    CrossrefPubMedGoogle Scholar
  • 59 Joensuu H, Wardelmann E, Eriksson M. et al. KIT and PDGFRA mutations and survival of gastrointestinal stromal tumor patients treated with adjuvant imatinib in a randomized trial. Clin Cancer Res 2023; 29 (17) 3313-3319
    CrossrefPubMedGoogle Scholar
  • 60 Joensuu H, Wardelmann E, Sihto H. et al. Effect of KIT and PDGFRA mutations on survival in patients with gastrointestinal stromal tumors treated with adjuvant imatinib: an exploratory analysis of a randomized clinical trial. JAMA Oncol 2017; 3 (05) 602-609
    CrossrefPubMedGoogle Scholar
  • 61 Casali PG, Le Cesne A, Velasco AP. et al. Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS)*. Ann Oncol 2021; 32 (04) 533-541
    CrossrefPubMedGoogle Scholar
  • 62 von Mehren M, Kane JM, Bui MM. et al. NCCN Guidelines insights: soft tissue sarcoma, version 1.2021. J Natl Compr Canc Netw 2020; 18 (12) 1604-1612
    CrossrefPubMedGoogle Scholar
  • 63 Liegl B, Kepten I, Le C. et al. Heterogeneity of kinase inhibitor resistance mechanisms in GIST. J Pathol 2008; 216 (01) 64-74
    CrossrefPubMedGoogle Scholar
  • 64 Antonescu CR, DeMatteo RP. CCR 20th Anniversary Commentary: a genetic mechanism of imatinib resistance in gastrointestinal stromal tumor-where are we a decade later?. Clin Cancer Res 2015; 21 (15) 3363-3365
    CrossrefPubMedGoogle Scholar
  • 65 Hemming ML, Lawlor MA, Zeid R. et al. Gastrointestinal stromal tumor enhancers support a transcription factor network predictive of clinical outcome. Proc Natl Acad Sci U S A 2018; 115 (25) E5746-E5755
    CrossrefPubMedGoogle Scholar
  • 66 Reichardt P, Demetri GD, Gelderblom H. et al. Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial. BMC Cancer 2016; 16: 22
    CrossrefPubMedGoogle Scholar
  • 67 Reichardt P, Kang YK, Rutkowski P. et al. Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib. Cancer 2015; 121 (09) 1405-1413
    CrossrefPubMedGoogle Scholar
  • 68 Guo T, Hajdu M, Agaram NP. et al. Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-3ins mutation: an in vitro mutagenesis screen for drug resistance. Clin Cancer Res 2009; 15 (22) 6862-6870
    CrossrefPubMedGoogle Scholar
  • 69 Nishida T, Takahashi T, Nishitani A. et al; Japanese Study Group on GIST. Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene. Int J Clin Oncol 2009; 14 (02) 143-149
    CrossrefPubMedGoogle Scholar
  • 70 Evans EK, Gardino AK, Kim JL. et al. A precision therapy against cancers driven by KIT/PDGFRA mutations. Sci Transl Med 2017; 9 (414) eaao1690
    CrossrefPubMedGoogle Scholar
  • 71 Gebreyohannes YK, Wozniak A, Zhai ME. et al. Robust activity of avapritinib, potent and highly selective inhibitor of mutated KIT, in patient-derived xenograft models of gastrointestinal stromal tumors. Clin Cancer Res 2019; 25 (02) 609-618
    CrossrefPubMedGoogle Scholar
  • 72 Heinrich MC, Jones RL, von Mehren M. et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol 2020; 21 (07) 935-946
    CrossrefPubMedGoogle Scholar
  • 73 Smith BD, Kaufman MD, Lu WP. et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell 2019; 35 (05) 738-751.e9
    CrossrefPubMedGoogle Scholar
  • 74 Janku F, Abdul Razak AR, Chi P. et al. Switch control inhibition of KIT and PDGFRA in patients with advanced gastrointestinal stromal tumor: a phase I study of ripretinib. J Clin Oncol 2020; 38 (28) 3294-3303
    CrossrefPubMedGoogle Scholar
  • 75 Basilio-de-Oliveira RP, Pannain VL. Prognostic angiogenic markers (endoglin, VEGF, CD31) and tumor cell proliferation (Ki67) for gastrointestinal stromal tumors. World J Gastroenterol 2015; 21 (22) 6924-6930
    CrossrefPubMedGoogle Scholar
  • 76 Gromova P, Rubin BP, Thys A, Cullus P, Erneux C, Vanderwinden JM. ENDOGLIN/CD105 is expressed in KIT positive cells in the gut and in gastrointestinal stromal tumours. J Cell Mol Med 2012; 16 (02) 306-317
    CrossrefPubMedGoogle Scholar
  • 77 Ditsiou A, Cilibrasi C, Simigdala N. et al. The structure-function relationship of oncogenic LMTK3. Sci Adv 2020; 6 (46) eabc3099
    CrossrefPubMedGoogle Scholar
  • 78 Klug LR, Bannon AE, Javidi-Sharifi N. et al. LMTK3 is essential for oncogenic KIT expression in KIT-mutant GIST and melanoma. Oncogene 2019; 38 (08) 1200-1210
    CrossrefPubMedGoogle Scholar
  • 79 Stecca B, Ruiz i Altaba A. Context-dependent regulation of the GLI code in cancer by Hedgehog and non-Hedgehog signals. J Mol Cell Biol 2010; 2 (02) 84-95
    CrossrefPubMedGoogle Scholar
  • 80 Duan Y, Haybaeck J, Yang Z. Therapeutic potential of PI3K/AKT/mTOR pathway in gastrointestinal stromal tumors: rationale and progress. Cancers (Basel) 2020; 12 (10) 2972
    CrossrefPubMedGoogle Scholar
  • 81 He W, Xu L, Ding J. et al. Co-targeting of ACK1 and KIT triggers additive anti-proliferative and -migration effects in imatinib-resistant gastrointestinal stromal tumors. Biochim Biophys Acta Mol Basis Dis 2023; 1869 (05) 166690
    CrossrefPubMedGoogle Scholar
  • 82 Boichuk S, Galembikova A, Dunaev P. et al. A novel receptor tyrosine kinase switch promotes gastrointestinal stromal tumor drug resistance. Molecules 2017; 22 (12) 2152
    CrossrefPubMedGoogle Scholar
  • 83 Boichuk S, Galembikova A, Dunaev P. et al. Targeting of FGF-signaling re-sensitizes gastrointestinal stromal tumors (GIST) to imatinib in vitro and in vivo. Molecules 2018; 23 (10) 2643
    CrossrefPubMedGoogle Scholar
  • 84 Chaix A, Arcangeli ML, Lopez S. et al. KIT-D816V oncogenic activity is controlled by the juxtamembrane docking site Y568-Y570. Oncogene 2014; 33 (07) 872-881
    CrossrefPubMedGoogle Scholar
  • 85 Wong M, Funasaka K, Obayashi T. et al. AMPD3 is associated with the malignant characteristics of gastrointestinal stromal tumors. Oncol Lett 2017; 13 (03) 1281-1287
    CrossrefPubMedGoogle Scholar
  • 86 Guérin A, Angebault C, Kinet S. et al. LIX1-mediated changes in mitochondrial metabolism control the fate of digestive mesenchyme-derived cells. Redox Biol 2022; 56: 102431
    CrossrefPubMedGoogle Scholar
  • 87 Guérin A, Martire D, Trenquier E. et al. LIX1 regulates YAP activity and controls gastrointestinal cancer cell plasticity. J Cell Mol Med 2020; 24 (16) 9244-9254
    CrossrefPubMedGoogle Scholar
  • 88 Ruiz-Demoulin S, Trenquier E, Dekkar S. et al. LIX1 controls MAPK signaling reactivation and contributes to GIST-T1 cell resistance to imatinib. Int J Mol Sci 2023; 24 (08) 7138
    CrossrefPubMedGoogle Scholar
  • 89 Xu K, He Z, Chen M. et al. HIF-1α regulates cellular metabolism, and Imatinib resistance by targeting phosphogluconate dehydrogenase in gastrointestinal stromal tumors. Cell Death Dis 2020; 11 (07) 586
    CrossrefPubMedGoogle Scholar
  • 90 Zhang T, Wang Y, Xie M. et al. HGF-mediated elevation of ETV1 facilitates hepatocellular carcinoma metastasis through upregulating PTK2 and c-MET. J Exp Clin Cancer Res 2022; 41 (01) 275
    CrossrefPubMedGoogle Scholar
  • 91 Cao L, Zheng K, Liu Y. et al. Identification of novel imatinib-resistant genes in gastrointestinal stromal tumors. Front Genet 2022; 13: 878145
    CrossrefPubMedGoogle Scholar
  • 92 Boichuk S, Lee DJ, Mehalek KR. et al. Unbiased compound screening identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors. Cancer Res 2014; 74 (04) 1200-1213
    CrossrefPubMedGoogle Scholar
  • 93 Farag S, Somaiah N, Choi H. et al. Clinical characteristics and treatment outcome in a large multicentre observational cohort of PDGFRA exon 18 mutated gastrointestinal stromal tumour patients. Eur J Cancer 2017; 76: 76-83
    CrossrefPubMedGoogle Scholar
  • 94 Kang HJ, Koh KH, Yang E. et al. Differentially expressed proteins in gastrointestinal stromal tumors with KIT and PDGFRA mutations. Proteomics 2006; 6 (04) 1151-1157
    CrossrefPubMedGoogle Scholar
  • 95 Wozniak A, Rutkowski P, Piskorz A. et al; Polish Clinical GIST Registry. Prognostic value of KIT/PDGFRA mutations in gastrointestinal stromal tumours (GIST): Polish Clinical GIST Registry experience. Ann Oncol 2012; 23 (02) 353-360
    CrossrefPubMedGoogle Scholar
  • 96 Indio V, Ravegnini G, Astolfi A. et al. Gene expression profiling of PDGFRA mutant GIST reveals immune signatures as a specific fingerprint of D842V exon 18 mutation. Front Immunol 2020; 11: 851
    CrossrefPubMedGoogle Scholar
  • 97 Bannon AE, Klug LR, Corless CL, Heinrich MC. Using molecular diagnostic testing to personalize the treatment of patients with gastrointestinal stromal tumors. Expert Rev Mol Diagn 2017; 17 (05) 445-457
    CrossrefPubMedGoogle Scholar
  • 98 Wang C, Yantiss RK, Lieberman MD. et al. A rare PDGFRA exon 15 germline mutation identified in a patient with phenotypic manifestations concerning for GIST-plus syndrome: a case report and review of literature. Int J Surg Pathol 2023; 31 (06) 1139-1145
    CrossrefPubMedGoogle Scholar
  • 99 von Mehren M, Joensuu H. Gastrointestinal stromal tumors. J Clin Oncol 2018; 36 (02) 136-143
    CrossrefPubMedGoogle Scholar
  • 100 Heinrich MC, Owzar K, Corless CL. et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol 2008; 26 (33) 5360-5367
    CrossrefPubMedGoogle Scholar
  • 101 Farag S, Smith MJ, Fotiadis N, Constantinidou A, Jones RL. Revolutions in treatment options in gastrointestinal stromal tumours (GISTs): the latest updates. Curr Treat Options Oncol 2020; 21 (07) 55
    CrossrefPubMedGoogle Scholar
  • 102 Grunewald S, Klug LR, Mühlenberg T. et al. Resistance to avapritinib in PDGFRA-driven GIST is caused by secondary mutations in the PDGFRA kinase domain. Cancer Discov 2021; 11 (01) 108-125
    CrossrefPubMedGoogle Scholar
  • 103 Teuber A, Schulz T, Fletcher BS. et al. Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA. Nat Commun 2024; 15 (01) 63
    CrossrefPubMedGoogle Scholar
  • 104 Pitsava G, Settas N, Faucz FR, Stratakis CA. Carney triad, Carney-Stratakis syndrome, 3PAS and other tumors due to SDH deficiency. Front Endocrinol (Lausanne) 2021; 12: 680609
    CrossrefPubMedGoogle Scholar
  • 105 Gill AJ. Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia. Pathology 2012; 44 (04) 285-292
    CrossrefPubMedGoogle Scholar
  • 106 Schipani A, Nannini M, Astolfi A, Pantaleo MA. SDHA germline mutations in SDH-deficient GISTs: a current update. Genes (Basel) 2023; 14 (03) 646
    CrossrefPubMedGoogle Scholar
  • 107 Elston MS, Sehgal S, Dray M. et al. A duodenal SDH-deficient gastrointestinal stromal tumor in a patient with a germline SDHB mutation. J Clin Endocrinol Metab 2017; 102 (05) 1447-1450
    CrossrefPubMedGoogle Scholar
  • 108 Moosavi B, Berry EA, Zhu XL, Yang WC, Yang GF. The assembly of succinate dehydrogenase: a key enzyme in bioenergetics. Cell Mol Life Sci 2019; 76 (20) 4023-4042
    CrossrefPubMedGoogle Scholar
  • 109 Kays JK, Sohn JD, Kim BJ, Goze K, Koniaris LG. Approach to wild-type gastrointestinal stromal tumors. Transl Gastroenterol Hepatol 2018; 3: 92
    CrossrefPubMedGoogle Scholar
  • 110 Nannini M, Rizzo A, Indio V, Schipani A, Astolfi A, Pantaleo MA. Targeted therapy in SDH-deficient GIST. Ther Adv Med Oncol 2021; 13: 17 588359211023278
    CrossrefPubMedGoogle Scholar
  • 111 Pantaleo MA, Lolli C, Nannini M. et al. Good survival outcome of metastatic SDH-deficient gastrointestinal stromal tumors harboring SDHA mutations. Genet Med 2015; 17 (05) 391-395
    CrossrefPubMedGoogle Scholar
  • 112 Gong QX, Ding Y, Zhang WM, Zhang JW, Zhang ZH. De novo dedifferentiated SDH-deficient gastrointestinal stromal tumor with MDM2 amplification: case report and literature review. Front Oncol 2023; 13: 1233561
    CrossrefPubMedGoogle Scholar
  • 113 Selak MA, Armour SM, MacKenzie ED. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell 2005; 7 (01) 77-85
    CrossrefPubMedGoogle Scholar
  • 114 Raimundo N, Baysal BE, Shadel GS. Revisiting the TCA cycle: signaling to tumor formation. Trends Mol Med 2011; 17 (11) 641-649
    CrossrefPubMedGoogle Scholar
  • 115 Raha S, McEachern GE, Myint AT, Robinson BH. Superoxides from mitochondrial complex III: the role of manganese superoxide dismutase. Free Radic Biol Med 2000; 29 (02) 170-180
    CrossrefPubMedGoogle Scholar
  • 116 Xiao M, Yang H, Xu W. et al. Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors. Genes Dev 2012; 26 (12) 1326-1338
    CrossrefPubMedGoogle Scholar
  • 117 Wu CE, Tzen CY, Wang SY, Yeh CN. Clinical diagnosis of gastrointestinal stromal tumor (GIST): from the molecular genetic point of view. Cancers (Basel) 2019; 11 (05) 679
    CrossrefPubMedGoogle Scholar
  • 118 Indio V, Schipani A, Nannini M. et al. Gene expression landscape of SDH-deficient gastrointestinal stromal tumors. J Clin Med 2021; 10 (05) 1057
    CrossrefPubMedGoogle Scholar
  • 119 Giger OT, Ten Hoopen R, Shorthouse D. et al. Preferential MGMT hypermethylation in SDH-deficient wild-type GIST. J Clin Pathol 2023; 77 (01) 34-39
    CrossrefPubMedGoogle Scholar
  • 120 Hong DS, DuBois SG, Kummar S. et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol 2020; 21 (04) 531-540
    CrossrefPubMedGoogle Scholar
  • 121 Weldon CB, Madenci AL, Boikos SA. et al. Surgical management of wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health Pediatric and Wildtype GIST Clinic. J Clin Oncol 2017; 35 (05) 523-528
    CrossrefPubMedGoogle Scholar
  • 122 Blay JY, Serrano C, Heinrich MC. et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2020; 21 (07) 923-934
    CrossrefPubMedGoogle Scholar
  • 123 Casali PG, Blay JY, Abecassis N. et al; ESMO Guidelines Committee, EURACAN and GENTURIS. Electronic address: clinicalguidelines@esmo.org. Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2022; 33 (01) 20-33
    CrossrefPubMedGoogle Scholar
  • 124 Cohen NA, Zeng S, Seifert AM. et al. Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors. Cancer Res 2015; 75 (10) 2061-2070
    CrossrefPubMedGoogle Scholar
  • 125 Serrano C, Mariño-Enríquez A, Tao DL. et al. Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. Br J Cancer 2019; 120 (06) 612-620
    CrossrefPubMedGoogle Scholar
  • 126 Flavahan WA, Drier Y, Johnstone SE. et al. Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs. Nature 2019; 575 (7781) 229-233
    CrossrefPubMedGoogle Scholar
  • 127 von Mehren M, George S, Heinrich MC. et al. Linsitinib (OSI-906) for the treatment of adult and pediatric wild-type gastrointestinal stromal tumors, a SARC phase II study. Clin Cancer Res 2020; 26 (08) 1837-1845
    CrossrefPubMedGoogle Scholar
  • 128 Glod J, Arnaldez FI, Wiener L. et al. A phase II trial of vandetanib in children and adults with succinate dehydrogenase-deficient gastrointestinal stromal tumor. Clin Cancer Res 2019; 25 (21) 6302-6308
    CrossrefPubMedGoogle Scholar
  • 129 Demetri GD, Reichardt P, Kang YK. et al; GRID study investigators. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013; 381 (9863) 295-302
    CrossrefPubMedGoogle Scholar
  • 130 Ben-Ami E, Barysauskas CM, von Mehren M. et al. Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy. Ann Oncol 2016; 27 (09) 1794-1799
    CrossrefPubMedGoogle Scholar
  • 131 Martin-Broto J, Valverde C, Hindi N. et al. REGISTRI: regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial. Mol Cancer 2023; 22 (01) 127
    CrossrefPubMedGoogle Scholar
  • 132 Lou L, Zhang W, Li J, Wang Y. Abnormal MGMT promoter methylation in gastrointestinal stromal tumors: genetic susceptibility and association with clinical outcome. Cancer Manag Res 2020; 12: 9941-9952
    CrossrefPubMedGoogle Scholar
  • 133 Nannini M, Urbini M, Astolfi A, Biasco G, Pantaleo MA. The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST). J Transl Med 2017; 15 (01) 113
    CrossrefPubMedGoogle Scholar
  • 134 Pantaleo MA, Urbini M, Indio V. et al. Genome-wide analysis identifies MEN1 and MAX mutations and a neuroendocrine-like molecular heterogeneity in quadruple WT GIST. Mol Cancer Res 2017; 15 (05) 553-562
    CrossrefPubMedGoogle Scholar
  • 135 Mei L, Smith SC, Faber AC. et al. Gastrointestinal stromal tumors: the GIST of precision medicine. Trends Cancer 2018; 4 (01) 74-91
    CrossrefPubMedGoogle Scholar
  • 136 Huss S, Pasternack H, Ihle MA. et al. Clinicopathological and molecular features of a large cohort of gastrointestinal stromal tumors (GISTs) and review of the literature: BRAF mutations in KIT/PDGFRA wild-type GISTs are rare events. Hum Pathol 2017; 62: 206-214
    CrossrefPubMedGoogle Scholar
  • 137 Agaram NP, Wong GC, Guo T. et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 2008; 47 (10) 853-859
    CrossrefPubMedGoogle Scholar
  • 138 Klug LR, Khosroyani HM, Kent JD, Heinrich MC. New treatment strategies for advanced-stage gastrointestinal stromal tumours. Nat Rev Clin Oncol 2022; 19 (05) 328-341
    CrossrefPubMedGoogle Scholar
  • 139 Jašek K, Váňová B, Grendár M. et al. BRAF mutations in KIT/PDGFRA positive gastrointestinal stromal tumours (GISTs): is their frequency underestimated?. Pathol Res Pract 2020; 216 (11) 153171
    CrossrefPubMedGoogle Scholar
  • 140 Torrence D, Xie Z, Zhang L, Chi P, Antonescu CR. Gastrointestinal stromal tumors with BRAF gene fusions. A report of two cases showing low or absent KIT expression resulting in diagnostic pitfalls. Genes Chromosomes Cancer 2021; 60 (12) 789-795
    CrossrefPubMedGoogle Scholar
  • 141 Gowda S, Sandow L, Heinrich MC. Treatment of BRAF V600E mutant gastrointestinal stromal tumor with dabrafenib: a case report. J Gastrointest Oncol 2024; 15 (02) 788-793
    CrossrefPubMedGoogle Scholar
  • 142 Nishida T, Tsujimoto M, Takahashi T, Hirota S, Blay JY, Wataya-Kaneda M. Gastrointestinal stromal tumors in Japanese patients with neurofibromatosis type I. J Gastroenterol 2016; 51 (06) 571-578
    CrossrefPubMedGoogle Scholar
  • 143 Agaimy A, Vassos N, Croner RS. Gastrointestinal manifestations of neurofibromatosis type 1 (Recklinghausen's disease): clinicopathological spectrum with pathogenetic considerations. Int J Clin Exp Pathol 2012; 5 (09) 852-862
    PubMedGoogle Scholar
  • 144 Arshad J, Ahmed J, Subhawong T, Trent JC. Progress in determining response to treatment in gastrointestinal stromal tumor. Expert Rev Anticancer Ther 2020; 20 (04) 279-288
    CrossrefPubMedGoogle Scholar
  • 145 Segawa K, Sugita S, Sugawara T. et al. Multiple gastrointestinal stromal tumors involving extragastrointestinal sites in neurofibromatosis type 1. Pathol Int 2018; 68 (02) 142-144
    CrossrefPubMedGoogle Scholar
  • 146 Burgoyne AM, De Siena M, Alkhuziem M. et al. Duodenal-jejunal flexure GI stromal tumor frequently heralds somatic NF1 and notch pathway mutations. JCO Precis Oncol 2017; 2017: PO.17.00014
    Google Scholar
  • 147 Mühlenberg T, Ketzer J, Heinrich MC. et al. KIT-dependent and KIT-independent genomic heterogeneity of resistance in gastrointestinal stromal tumors - TORC1/2 inhibition as salvage strategy. Mol Cancer Ther 2019; 18 (11) 1985-1996
    CrossrefPubMedGoogle Scholar
  • 148 Park EK, Kim HJ, Lee YH, Koh YS, Hur YH, Cho CK. Synchronous gastrointestinal stromal tumor and ampullary neuroendocrine tumor in association with neurofibromatosis type 1: a report of three cases. Korean J Gastroenterol 2019; 74 (04) 227-231
    CrossrefPubMedGoogle Scholar