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KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance

Oncogene volume 26, pages 6386–6395 (2007)Cite this article

Abstract

Most gastrointestinal stromal tumors (GISTs) express oncogenic and constitutively active forms of the KIT or platelet-derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinase proteins, and these kinase oncoproteins serve as targets for effective therapies. Given that mutant KIT oncoproteins serve crucial transforming roles in GISTs, we evaluated interactions with the KIT oncoproteins and determined signaling pathways that are dependent on KIT oncogenic activation in GISTs. Tyrosine-phosphorylated KIT oncoproteins interacted with PDGFRA, PDGFRB, phosphatidylinositol 3-kinase (PI3-K) and PKCθ in GIST cells, and these interactions were abolished by KIT inhibition with imatinib or PKC412 or KIT RNAi. Notably, tyrosine-phosphorylated PDGFRA was prominent in frozen GIST tumors expressing KIT oncoproteins, suggesting that KIT-mediated PDGFRA phosphorylation is an efficient and biologically consequential mechanism in GISTs. Activated signaling intermediates were identified by immunoaffinity purification of tyrosine-phosphorylated proteins in GIST cells before and after treatment with KIT inhibitors, and these analyses show that GRB2, SHC, CBL and MAPK activation are largely KIT dependent in GISTs, whereas PI3-K, STAT1 and STAT3 activation are partially KIT dependent. In addition, we found that phosphorylation of several tyrosine kinase proteins – including JAK1 and EPHA4 – did not depend on KIT activation. Likewise, paxillin activation was independent of the KIT oncogenic signal. These studies identify signaling pathways that can provide both KIT-dependent and KIT-independent therapeutic synergies in GIST, and thereby highlight clinical strategies that might consolidate GIST therapeutic response to KIT/PDGFRA inhibition.

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Acknowledgements

We thank Yongchun Zhou for critical review of the article and valuable discussions, Chang-Jie Chen, Anette Duensing and Maureen Thyne for useful discussions and technical assistance. This work was supported by grants from an anonymous donor, the Life Raft Group, Cesarini Team for the Pan-Massachusetts Challenge, 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.

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Authors and Affiliations

  1. Department of Pathology, Brigham & Women's Hospital, Boston, MA, USA

    M-J Zhu, W-B Ou, C D M Fletcher & J A Fletcher

  2. Departments of Pathology, Pediatrics and Medicine, Harvard Medical School, Boston, MA, USA

    M-J Zhu, W-B Ou, C D M Fletcher, G D Demetri & J A Fletcher

  3. Novartis Oncology, Florham Park, NJ, USA

    P S Cohen

  4. Ludwig Center at Dana-Farber Cancer Institute, Boston, MA, USA

    G D Demetri

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  1. M-J Zhu
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  2. W-B Ou
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  3. C D M Fletcher
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  4. P S Cohen
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  5. G D Demetri
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  6. J A Fletcher
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Correspondence to M-J Zhu 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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Zhu, MJ., Ou, WB., Fletcher, C. et al. KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance. Oncogene 26, 6386–6395 (2007). https://doi.org/10.1038/sj.onc.1210464

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