Imatinib resistance and microcytic erythrocytosis in a Kit(V558Δ;T669I/+) gatekeeper-mutant mouse model of gastrointestinal stromal tumor Journal Article

Authors: Bosbach, B.; Deshpande, S.; Rossi, F.; Shieh, J.H.; Sommer, G.; de Stanchina, E.; Veach, D. R.; Scandura, J. M.; Manova-Todorova, K.; Moore, M. A. S.; Antonescu, C. R.; Besmer, P.
Article Title: Imatinib resistance and microcytic erythrocytosis in a Kit(V558Δ;T669I/+) gatekeeper-mutant mouse model of gastrointestinal stromal tumor
Abstract: Most gastrointestinal stromal tumors (GISTs) harbor a gain-of-function mutation in the Kit receptor. GIST patients treated with the tyrosine kinase inhibitor imatinib frequently develop imatinib resistance as a result of second-site Kit mutations. To investigate the consequences of second-site Kit mutations on GIST development and imatinib sensitivity, we engineered a mouse model carrying in the endogenous Kit locus both the Kit V558Δ mutation found in a familial case of GIST and the Kit T669I (human KIT T670I) "gatekeeper"mutation found in imatinib-resistant GIST patients. Similar to Kit V558Δ/+ mice, Kit V558Δ;T669I/+ mice developed gastric and colonic interstitial cell of Cajal hyperplasia as well as cecal GIST. In contrast to the single-mutant Kit V558Δ/+ control mice, treatment of the Kit V558Δ;T669I/+ mice with either imatinib or dasatinib failed to inhibit oncogenic Kit signaling and GIST growth. However, this resistance could be overcome by treatment of Kit V558Δ;T669I/+ mice with sunitinib or sorafenib. Although tumor lesions were smaller in Kit V558Δ;T669I/+ mice than in single-mutant mice, both interstitial cell of Cajal hyperplasia and mast cell hyperplasia were exacerbated in Kit V558Δ;T669I/+ mice. Strikingly, the Kit V558Δ;T669I/+ mice developed a pronounced polycythemia vera-like erythrocytosis in conjunction with microcytosis. This mouse model should be useful for preclinical studies of drug candidates designed to overcome imatinib resistance in GIST and to investigate the consequences of oncogenic KIT signaling in hematopoietic as well as other cell lineages.
Keywords: signal transduction; controlled study; treatment failure; gene mutation; disease course; sorafenib; sunitinib; nonhuman; mouse; gastrointestinal stromal tumor; imatinib; erythropoiesis; animal experiment; animal model; drug resistance; dasatinib; soft tissue sarcoma; hematopoiesis; drug sensitivity; oncogene c kit; erythrocytosis; microcytosis
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 109
Issue: 34
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 2012-08-21
Start Page: E2276
End Page: E2283
Language: English
DOI: 10.1073/pnas.1115240109
PROVIDER: scopus
PMCID: PMC3427109
PUBMED: 22652566
Notes: --- - "Export Date: 1 October 2012" - "CODEN: PNASA" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Darren Veach
    76 Veach
  2. Cristina R Antonescu
    746 Antonescu
  3. Jae-Hung Shieh
    76 Shieh
  4. Ferdinando Rossi
    23 Rossi
  5. Malcolm A S Moore
    526 Moore
  6. Peter Besmer
    114 Besmer
  7. Benedikt Bosbach
    10 Bosbach