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KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway

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.

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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.

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Correspondence to S Bauer or J A Fletcher.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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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

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