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Molecular mechanisms of primary and secondary resistance, molecular-genetic features and characteristics of KIT/PDGFRA non-mutated GISTs


Authors: Alena Kalfusová;  Roman Kodet
Authors‘ workplace: Ústav patologie a molekulární medicíny, 2. LF UK a FN Motol, Praha
Published in: Čes.-slov. Patol., 53, 2017, No. 4, p. 167-173
Category: Reviews Article

Overview

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Most of them arise due to activating mutations in KIT (75 – 85 %) or PDGFRA (less than 10 %) genes. Identification of the activating mutations in KIT and PDGFRA genes, which code for receptor tyrosine kinases (RTKs), has improved the outcome of targeted therapy of metastatic, unresectable or recurrent GISTs. Primary and/or secondary resistance represents a significant problem in the targeted therapy by Imatinib mesylate (IM) in patients with GIST. An important mechanism of the secondary resistance is the evolvement of secondary mutations. Except for primary and secondary resistance, there is another problem of disease progression - a failure of tumor cells eradication even in the long term therapy of tyrosine kinase inhibitors. GISTs without mutations in KIT/PDGFRA genes constitute 10 - 15% GISTs in adults, and a majority (85 %) of pediatric GISTs. KIT/PDGFRA wild-type GISTs represent a heterogeneous group of tumors with several molecular-genetics and/or morphologic differences. KIT/PDGFRA wild-type GISTs are different in their molecular features, for example in mutations in the BRAF, KRAS, NF1 genes or defects of succinate dehydrogenase (SDH) subunits. KIT/PDGFRA wild-type GISTs are generally less sensitive to targeted therapy by tyrosine kinase inhibitors in comparison with KIT/PDGFRA mutated GISTs. Inhibitors of BRAF, PI3K (mTOR) or inhibitors of IGF1R and VEGFR receptors provide alternative therapeutic strategies.

Keywords:
GIST – primary and secondary resistance – KIT/PDGFRA non mutated GISTs – SDH complex – BRAF mutations – IGH system


Sources

1. Ordog T, Zörnig M, Hayashi Y. Targeting disease persistance in gastrointestinal stromal tumors. Stem Cells Trans Med 2015; 4: 702-707.

2. Corless CL. Gastrointestinal stromal tumors: what do we know now? Mod Pathol 2014; 27: S1-S16.

3. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations of c-kit gene in human gastrointestinal stromal tumors. Science 1998; 279: 577-580.

4. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003; 299: 708-710.

5. Drucker BJ, Tamura S, Buchdunker E, et al. Effects of a selective inhibitor of the abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Medicine 1996; 2(5): 561-566.

6. Al Ali HK, Heinrich MC, Lange T, et al. High incidence of BCR-ABL kinase domain mutations and absence of mutations of the PDGFR and KIT activation loops in CML patiens with secondary resistance to imatinib. Hematol J 2004; 5(1): 55-60.

7. Gorre ME, Mohhamed M, Ellwood K, et al. Clinical resistence to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876-880.

8. Antonescu CR, Besmer P, Guo T, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 2005; 11: 4182-4190.

9. Augustiňáková A, Kodet R. Molekulární diagnostika gastrointestinálních stromálních tumorů ve vztahu k predikci terapeutické odpovědi na cílenou biologickou léčbu. Cesk Patol 2011; 47(4): 148-152.

10. Gounder MM, Maki RG. Molecular basis for primary and secondary tyrosine kinase inhibitor resistance in gastrointestinal stromal tumor. Cancer Chemother Pharmacol 2011; 67(Suppl 1): 25-43.

11. Heinrich MC. Molecular basis for treatment of gastrointestinal stromal tumours. EJC Supplements 2006; 10-16.

12. Nishida T, Kanda T, Nishitani A, et al. Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor. Cancer Sci 2008; 99(4): 799-804.

13. Gramza AW, Corless CL, Heinrich MC. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Cancer Res 2009; 15(24): 7510-7518.

14. Agaram NP, Besmer P, Wong GC, et al. Pathologic and molecular heterogenity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors. Clin Cancer Res 2007; 13: 170-181.

15. Wardelmann E, Thomas N, Merkelbach-Bruse S, et al. Acquired resistance to imatinib in gastrointestinal stromal tumors caused by multiple KIT mutations. Lancet Oncol 2005; 6: 249-251.

16. Liegl B, Kepten I, Le C, et al. Heterogenity of kinase inhibitor resistance mechanisms in GIST. J Pathol 2008; 216(1): 64-74.

17. Wardelmann E, Merkelbach-Bruse S, Pauls K, et al. Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 2006; 12(6): 1743-1749.

18. Maleddu A, Pantaleo MA, Nannini M, et al. Mechanisms of secondary resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors (Review). Oncology Reports 2009; 21: 1359-1366.

19. Antonescu CR, Romeo S, Zhang L, et al. Dedifferentiation in gastrointestinal stromal tumor to an anaplastic KIT negative phenotype – a diagnostic pitfall. Morphologic and molecular characterization of 8 cases occuring either de-novo or after imatinib therapy. J Am Surg Pathol 2013; 37(3): 385-392.

20. 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.

21. Zheng S, Huang K, Jia J, et al. Rhabdomyosarcomatous differentiation in gastrointestinal stromal tumors after imatinib resistance: a potential diagnostic pitfall. Exp Biol Med 2013; 238: 120-124.

22. 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.

23. Daum O, Šedivcová M. Gastrointestinální stromální tumor (GIST): Pokroky do roku 2013. Cesk Pathol 2014; 50(2): 76-80.

24. Hostein I, Faur N, Primois Ch, et al. BRAF mutation status in gastrointestinal stromal tumors. Am J Clin Pathol 2010; 133: 141-148.

25. Rossi S, Sbaraglia M, Campo Dell´Orto M, et al. Concomitant KIT/BRAF and PDGFRA/BRAF mutations are rare events in gastrointestinal stromal tumors. Oncotarget 2016; 7(21): 30109-30118.

26. Agaimy A, Terracciano LM, Dirnhofer S, et al. V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumor. J Clin Pathol 2009; 62: 613-616.

27. Miranda C, Nucifora M, Molinari F, et al. KRAS and BRAF mutations predict primary resistance to imatinib in gastrointestinal stromal tumors. Clin Cancer Res 2012; 18(6): 1769-1776.

28. Daniels M, Lurkin I, Pauli R, et al. Spectrum of KIT/PDGFRA/BRAF mutations and phosphatydilinositol-3-kinase pathway gene alterations in gastrointestinal stromal tumors (GIST). Cancer Lett 2011; 312(1): 43-54.

29. Belinsky MG, Skorobogatko YV, Rink L, et al. High density DNA array analysis reveals distinct genomic profiles in a subset of gastrointestinal stromal tumors. Genes Chromosomes Cancer 2009; 48(10): 886-896.

30. Lasota J, Xi L, Coates T, et al. No KRAS mutations found in gastrointestinal stromal tumors (GISTs): molecular genetic study of 514 cases. Mod Pathol 2013; 26: 1488-1491.

31. Beadling C, Patterson J, Justusson E, et al. Gene expression of the IGF pathway family distinguishes subsets of gastrointestinal stromal tumors wild type or KIT and PDGFRA. Cancer Med 2013; 2(1): 21-31.

32. Miettinen M, Lasota J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) – a review. Int J Biochem Cell Biol 2014; 53: 514-519.

33. Wang YM, Gu Ml, Ji F. Succinate dehydrogenase-deficient gastrointestinal stromal tumors. World J Gastroenterol 2015; 21(8): 2303-2314.

34. Tornillo L. Gastrointestinal stromal tumor – envolving concept. Front Medicine 2014; 1:43.

35. Pantaleo MA, Astolfi A, Urbini M, et al. Analysis of all subunits, SDHA, SDHB, SDHC, and SDHD of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST. Eur J Hum Genet 2014; 22(1): 32-39.

36. Celestino L, Lima J, Faustino A, et al. Molecular alterations and expression of succinate dehydrogenase complex in wild-type KIT/PDGFRA/BRAF gastrointestinal stromal tumors. Eur J Hum Genet 2013; 21(5): 503-510.

37. Lasota J, Wang Z, Kim SY, et al. Expression of the receptor type 1 insuline-like growth factor (IGF1R) in gastrointestinal stromal tumor. An immunohistochemical study of 1078 cases with diagnostic and therapeutic implications. Am J Surg Pathol 2013; 37(1): 114-119.

38. Janeway KA, Zhu MJ, Barretina J, et al. Strong expression of IGF1R in pediatric gastrointestinal stromal tumors without IGF1R genomic amplification. Int J Cancer 2010; 127(11): 2718-2722.

39. Belinski MG, Rink L, Cai KQ, et al. Somatic loss of function mutations in neurofibromin 1 and MYC associated factor X genes identified by exome-wide sequencing in a wild-type GIST case. BMC Cancer 2015; 15: 887.

40. Zhao X, Yue Ch. Gastrointestinal stromal tumor. J Gastrointest Oncol 2012; 3(3): 189-208.

41. Bajciova V. Pediatrický GIST. Onkologie 2016; 10(5): 218-223.

42. Garner AP, Gozgit JM, Anjum R, et al. Ponatinib inhibits polyclonal drug-resistent KIT oncoproteins and shows therapeutic potential in heavily pretreated gastrointestinal stromal tumor (GIST) patients. Clin Cancer Res 2014; 20(22): 5745-5755.

43. Schroeder B, Li Z, Cranmer LD, et al. Targeting gastrointestinal stromal tumors: the role of regorafenib. Onco Targets Ther 2016; 9: 3009-3016.

44. George S, Wang Q, Heinrich MC, et al. Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial. J Clin Oncol 2012; 30(19): 2401-2407.

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