Abstract
Most gastrointestinal stromal tumor (GIST) patients respond to KIT inhibition with imatinib, yet will eventually exhibit resistance. Imatinib-resistance mechanisms are heterogeneous, and little is known about KIT functional roles in imatinib-resistant GIST. Biological consequences of biochemical inhibition of KIT, phosphatidyl-inositol-3-kinase (PI3-K), PLCγ, MAPK/ERK kinase/mitogen-activated protein kinase (MEK/MAPK), mammalian target of rapamycin (mTOR) and JAK were determined by immunoblotting for protein activation, and by cell proliferation and apoptosis assays in GIST cell lines from imatinib-sensitive GIST (GIST882), imatinib-resistant GISTs (GIST430 and GIST48) and KIT-negative GIST (GIST62). KIT activation was 3- to 6-fold higher in GIST430 and GIST48 than in GIST882, whereas total KIT expression was comparable in these three GIST lines. In addition to the higher set point for KIT activation, GIST430 and GIST48 had intrinsic imatinib resistance. After treatment with 1 μ M imatinib, residual KIT activation was 6- and 2.8-fold higher in GIST430 and GIST48, respectively, compared to GIST882. In all GIST lines, cell growth arrest resulted from PI3-K inhibition, and – to a lesser extent – from MEK/MAPK and mTOR inhibition. Inhibition of JAK/STAT or PLCγ did not affect cell proliferation. Similarly, only PI3-K inhibition resulted in substantial apoptosis in the imatinib-resistant GISTs. We conclude that GIST secondary KIT mutations can be associated with KIT hyperactivation and imatinib resistance. Targeting critical downstream signaling proteins, such as PI3-K, is a promising therapeutic strategy in imatinib-resistant GISTs.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B et al. (2005). Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11: 4182–4190.
Bauer S, Hartmann JT, de Wit M, Lang H, Grabellus F, Antoch G et al. (2005a). Resection of residual disease in patients with metastatic gastrointestinal stromal tumors responding to treatment with imatinib. Int J Cancer 117: 316–325.
Bauer S, Hubert C, Heinrich MC, Cohen PS, Bertagnolli MM, Demetri GD et al. (2005b). KIT hyperactivation in imatinib-resistant GIST: implications for salvage therapies. Proc Am Soc Clin Oncol 23: a9034.
Bauer S, Yu LK, Demetri GD, Fletcher JA . (2006). Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res 66: 9153–9161.
Cammenga J, Horn S, Bergholz U, Sommer G, Besmer P, Fiedler W et al. (2005). Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate. Blood 106: 3958–3961.
Carter TA, Wodicka LM, Shah NP, Velasco AM, Fabian MA, Treiber DK et al. (2005). Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci USA 102: 11011–11016.
Corless CL, McGreevey L, Haley A, Town A, Heinrich MC . (2002). KIT mutations are common in incidental gastrointestinal stromal tumors one centimeter or less in size. Am J Pathol 160: 1567–1572.
Debiec-Rychter M, Cools J, Dumez H, Sciot R, Stul M, Mentens N et al. (2005). Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 128: 270–279.
Dematteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF . (2000). Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 231: 51–58.
Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J et al. (2006). Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 14: 1329–1338.
Demetri GD, Von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ et al. (2002). Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347: 472–480.
Duensing A, Medeiros F, McConarty B, Joseph NE, Panigrahy D, Singer S et al. (2004). Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 23: 3999–4006.
Fletcher JA, Corless CL, Dimitrijevic S, Von Mehren B, Eisenberg B, Joensuu H et al. (2003). Mechanisms of resistance to imatinib mesylate (IM) in advanced gastrointestinal stromal tumor (GIST). Proc Am Soc Clin Oncol 22: a3275.
Frank DA . (1999). STAT signaling in the pathogenesis and treatment of cancer. Mol Med 5: 432–456.
Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ et al. (2006). Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24: 4764–4774.
Heinrich MC, Corless CL, Demetri GD, Blanke CD, Von Mehren M, Joensuu H et al. (2003). Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21: 4342–4349.
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S et al. (1998). Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279: 577–580.
Linnekin D . (1999). Signaling pathways activated by c-Kit in hematopoietic cells. Int J Biochem Cell Biol 31: 1053–1074.
Mohi MG, Boulton C, Gu TL, Sternberg DW, Neuberg D, Griffin JD et al. (2004). Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA 101: 3130–3135.
Ning ZQ, Li J, McGuinness M, Arceci RJ . (2001). STAT3 activation is required for Asp(816) mutant c-Kit induced tumorigenicity. Oncogene 20: 4528–4536.
Rossi F, Ehlers I, Agosti V, Socci ND, Viale A, Sommer G et al. (2006). Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor. Proc Natl Acad Sci USA 103: 12843–12848.
Rubin BP, Singer S, Tsao C, Duensing A, Lux ML, Ruiz R et al. (2001). KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res 61: 8118–8121.
Sawka-Verhelle D, Tartare-Deckert S, Decaux JF, Girard J, Van Obberghen E . (2000). Stat 5B, activated by insulin in a Jak-independent fashion, plays a role in glucokinase gene transcription. Endocrinology 141: 1977–1988.
Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL . (2004). Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305: 399–401.
Shivakrupa R, Bernstein A, Watring N, Linnekin D . (2003). Phosphatidylinositol 3'-kinase is required for growth of mast cells expressing the kit catalytic domain mutant. Cancer Res 63: 4412–4419.
Tuveson DA, Willis NA, Jacks T, Griffin JD, Singer S, Fletcher CD et al. (2001). STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 20: 5054–5058.
Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY et al. (2004). Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet 364: 1127–1134.
Wardelmann E, Merkelbach-Bruse S, Pauls K, Thomas N, Schildhaus HU, Heinicke T et al. (2006). Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate. Clin Cancer Res 12: 1743–1749.
Wardelmann E, Thomas N, Merkelbach-Bruse S, Pauls K, Speidel N, Buttner R et al. (2005). Acquired resistance to imatinib in gastrointestinal stromal tumours caused by multiple KIT mutations. Lancet Oncol 6: 249–251.
Acknowledgements
SB was supported by a fellowship of the Deutsche Krebshilfe foundation. This work was also supported by an anonymous donor; grants from the Life Raft Group, Cesarini Team for the Pan-Massachusetts Challenge, and the Virginia and Daniel K Ludwig Trust for Cancer Research; the Ronald O Perelman Fund for Cancer Research; the Stutman GIST Cancer Research Fund; the Rubenstein Foundation and Leslie's Links. Imatinib and RAD001 (everolimus) were kindly provided by the Novartis Institutes for BioMedical Research. We thank Heidi Lane for extremely useful discussions of the manuscript. This work has been presented in part at the 2005 American Society of Clinical Oncology annual meeting.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
Supplementary information
Rights and permissions
About this article
Cite this article
Bauer, S., Duensing, A., Demetri, G. et al. KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene 26, 7560–7568 (2007). https://doi.org/10.1038/sj.onc.1210558
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1210558
Keywords
This article is cited by
-
The microphthalmia-associated transcription factor is involved in gastrointestinal stromal tumor growth
Cancer Gene Therapy (2023)
-
Molekularpathologisch determinierte multimodale Therapie gastrointestinaler Stromatumoren
Die Onkologie (2023)
-
Molekularpathologisch determinierte multimodale Therapie gastrointestinaler Stromatumoren
Wiener klinisches Magazin (2023)
-
TKI Treatment Sequencing in Advanced Gastrointestinal Stromal Tumors
Drugs (2023)
-
A multicenter, dose-finding, phase 1b study of imatinib in combination with alpelisib as third-line treatment in patients with advanced gastrointestinal stromal tumor
BMC Cancer (2022)