Abstract
Imatinib has revolutionized the treatment of GIST since this drug is able to inhibit tumoral growth by blocking the activity of receptor tyrosine kinases, KIT or PDGFRA, that in these tumors are constitutively activated because of the presence of mutations that alters their catalytic activity. However, despite this enormous improvement in the RFS and OS and in the quality of life of GIST patients, imatinib is not able to eradicate the disease: recurrences occur and acquired resistance is a common event which develops during targeted treatments. Several mechanisms have been demonstrated to be responsible for tumoral growth reactivation which is due to the reactivation of the altered KIT/PDGFRA receptors, no more blocked by the drug. Secondary point mutations are generally observed in the regrowing tumors, and it has been demonstrated that they alter the architectural structure of the site in which the interaction between the drug and the receptor happens. Other mechanisms causing drug resistance have been investigated, indicating that many aspects need to be still explicated and fully understood in order to define a strategy able to fight definitively GIST growth.
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References
Agaram NP, Wong GC, Guo T et al (2008) Novel V600E Braf mutations in imatinib-naïve and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 47:853–859
Antonescu CR, Besmer P, Guo T et al (2005) Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11(11):4182–4190
Boichuk S, Parry JA, Makielski KR et al (2013) The DREAM complex mediates GIST cell quiescence and is a novel therapeutic target to enhance imatinib-induced apoptosis. Cancer Res 73(16):5120–5129
Conca E, Negri T, Gronchi A et al (2009) Activate and resist: L576P-KIT in GIST. Mol Cancer Ther 8(9):2491–2495
El-Khattouti A, Selimovic D, Haikel Y et al (2013) Crosstalk between apoptosis and autophagy: molecular mechanisms and therapeutic strategies in cancer. J Cell Death 6:37–55
Gupta A, Roy S, Lazar AJ et al (2010) Autophagy inhibition and antimalarials promote cell death in gastrointestinal stromal tumor (GIST). Proc Natl Acad Sci U S A 107(32):14333–14338
Heinrich MC, Corless CL, Duensing A et al (2003) Pdgfra activating mutations in gastrointestinal stromal tumors. Science 299:708–710
Heinrich MC, Owzar K, Corless CL et al (2008) 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 26:5360–5367
Hirata E, Girotti MR, Viros A et al (2015) Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell 27(4):574–588
Hirota S, Isozaki K, Moriyama Y et al (1998) Gain-of-function mutations of C-kit in human gastrointestinal stromal tumors. Science 279:577–580
Janeway KA, Kim SY, Lodish M et al (2011) Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A 108(1):314–318
Joensuu H, Eriksson M, Sundby Hall K et al (2012) One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA 307:1265–1272
Kee D, Zalcberg JR (2012) Current and emerging strategies for the management of imatinib-refractory advanced gastrointestinal stromal tumors. Ther Adv Med Oncol 4(5):255–270
Lasota J, Felisiak-Golabek A, Wasag B et al (2016) Frequency and clinicopathologic profile of PIK3CA mutant GISTs: molecular genetic study of 529 cases. Mod Pathol 29:275–282
Liang L, Yan XE, Yin Y et al (2016) Structural and biochemical studies of the PDGFRA kinase domain. Biochem Biophys Res Commun 477(4):667–672
Mahadevan D, Cooke L, Riley C et al (2007) A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene 26(27):3909–3919
Miettinen M, Lasota J (2006) Gastrointestinal stromal tumors: review on morphology, molecular pathology, prognosis, and differential diagnosis. Arch Pathol Lab Med 130(10):1466–1478
Miettinen M, Wang ZF, Lasota J (2009) DOG1 antibody in the differential diagnosis of gastrointestinal stromal tumors: a study of 1840 cases. Am J Surg Pathol 33(9):1401–1408
Miranda C, Nucifora M, Molinari F et al (2012) KRAS and BRAF mutations predict primary resistance to imatinib in gastrointestinal stromal tumors. Clin Cancer Res 18(6):1769–1776
Miselli FC, Casieri P, Negri T et al (2007) c-Kit/PDGFRA gene status alterations possibly related to primary imatinib resistance in gastrointestinal stromal tumors. Clin Cancer Res 13(8):2369–2377
Miselli F, Negri T, Gronchi A et al (2008) Is autophagy rather than apoptosis the regression driver in imatinib-treated gastrointestinal stromal tumors? Transl Oncol 1(4):177–186
Pierotti MA, Tamborini E, Negri T et al (2011) Targeted therapy in GIST: in silico modeling for prediction of resistance. Nat Rev Clin Oncol 8(3):161–170
Ravegnini G, Sammarini G, Nannini M et al (2017) Gastrointestinal stromal tumors (GIST): facing cell death between autophagy and apoptosis. Autophagy 13(3):452–463
Tamborini E, Rossi S, Tarantino E et al (2012) Platelet-derived growth factor receptor alpha expression improves the diagnostic assessment of gastrointestinal stromal tumours. Histopathology 61(6):1240–1245
Wardelmann E, Merkelbach-Bruse S, Pauls K et al (2006) Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 12(6):1743–1749
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Tamborini, E. (2017). Mechanism of Resistance in Gastrointestinal Stromal Tumors. In: Mandalà , M., Romano, E. (eds) Mechanisms of Drug Resistance in Cancer Therapy. Handbook of Experimental Pharmacology, vol 249. Springer, Cham. https://doi.org/10.1007/164_2017_74
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DOI: https://doi.org/10.1007/164_2017_74
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