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Imatinib Resistance and Microcytic Erythrocytosis in a Kit Gatekeeper-Mutant Mouse Model of Gastrointestinal Stromal Tumor

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Imatinib Resistance and Microcytic Erythrocytosis in a Kit Gatekeeper-Mutant Mouse Model of Gastrointestinal Stromal Tumor Imatinib resistance and microcytic erythrocytosis in PNAS PLUS Δ a KitV558 ;T669I/+ gatekeeper-mutant mouse model of gastrointestinal stromal tumor Benedikt Bosbacha, Shayu Deshpandea, Ferdinand Rossia, Jae-Hung Shiehb, Gunhild Sommerc, Elisa de Stanchinad, Darren R. Veachd, Joseph M. Scandurae, Katia Manova-Todorovaa, Malcolm A. S. Mooreb, Cristina R. Antonescuf, and Peter Besmera,1 aDevelopmental Biology, bCell Biology, and dMolecular Pharmacology and Chemistry Programs, Sloan-Kettering Institute, New York, NY 10065; fDepartment of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065; cDepartment of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425; and eDepartment of Medicine, Weill Cornell Medical College, New York, NY 10065 Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved May 4, 2012 (received for review September 20, 2011) Most gastrointestinal stromal tumors (GISTs) harbor a gain-of- resistant to inhibition by imatinib. Imatinib binds to the inactive function mutation in the Kit receptor. GIST patients treated with conformation of the ABL and KIT kinases and not to the active the tyrosine kinase inhibitor imatinib frequently develop imatinib conformation and inhibits juxtamembrane domain KIT mutants resistance as a result of second-site Kit mutations. To investigate but not activation-loop KIT mutants (7). the consequences of second-site Kit mutations on GIST development That oncogenic KIT mutations have a critical role in the de- and imatinib sensitivity, we engineered a mouse model carrying in velopment of human neoplasias was strengthened by the obser- Δ the endogenous Kit locus both the KitV558 mutation found in a vation of familial GIST and familial mastocytosis (8). Patients familial case of GIST and the KitT669I (human KITT670I) “gatekeeper” with familial GIST also may have cutaneous mastocytosis and mutation found in imatinib-resistant GIST patients. Similar to hyperpigmentation. The observation of germ-line KIT gain-of- Δ Δ KitV558 /+ mice, KitV558 ;T669I/+ mice developed gastric and colonic function mutations provided us with a rationale for developing interstitial cell of Cajal hyperplasia as well as cecal GIST. In contrast a mouse model for familial GIST. The KIT-V558 deletion mu- V558Δ/+ to the single-mutant Kit control mice, treatment of the tation found in the first familial GIST case was introduced into MEDICAL SCIENCES V558Δ;T669I/+ Kit mice with either imatinib or dasatinib failed to in- the mouse genome using a knockin strategy (9). The mutant hibit oncogenic Kit signaling and GIST growth. However, this re- animals developed ICC hyperplasia and neoplastic lesions in the V558Δ;T669I/+ sistance could be overcome by treatment of Kit mice cecum indistinguishable from human GIST with complete pen- with sunitinib or sorafenib. Although tumor lesions were smaller etrance (10, 11). V558Δ;T669I/+ in Kit mice than in single-mutant mice, both interstitial Long-term imatinib treatment of GIST and of patients who cell of Cajal hyperplasia and mast cell hyperplasia were exacerbated have CML is associated with the development of drug resistance. V558Δ;T669I/+ V558Δ;T669I/+ in Kit mice. Strikingly, the Kit mice developed In GIST most cases of resistance appear to derive from second- a pronounced polycythemia vera-like erythrocytosis in conjunction site mutations in the kinase domain of the KIT receptor (12, 13). with microcytosis. This mouse model should be useful for pre- In patients who have CML, second-site mutations in BCR-ABL clinical studies of drug candidates designed to overcome imatinib are the predominant mechanism of drug resistance (14, 15). The resistance in GIST and to investigate the consequences of onco- second-site mutations in acquired imatinib-resistant GIST tend genic KIT signaling in hematopoietic as well as other cell lineages. to be single amino acid substitutions in KIT, located on the allele with the primary mutation (12, 16). Second-site mutations in soft tissue sarcoma | hematopoiesis | erythropoiesis | drug resistance GIST occur in catalytic domain II of KIT, exons 17 and 18, as well as in the N-terminal kinase domain, exon 13 (V654A) and astrointestinal stromal tumor (GIST) is the most common exon 14 (T670I) (12). In the gatekeeper T670I mutation, the Gmesenchymal tumor of the gastrointestinal tract. GISTs isoleucine methyl group protrudes into the imatinib binding site express receptor tyrosine kinase KIT and are thought to derive and disrupts an important hydrogen bond formation between + low from a KIT or KIT interstitial cell of Cajal (ICC) progenitor imatinib and the kinase, precluding proper binding of imatinib or from ICCs themselves (1). The principal genetic events re- (7). Second-site mutations in the activation loop within the kinase sponsible for the pathogenesis of GIST are thought to be gain-of- domain stabilize the active conformation of KIT and maintain it function mutations in the KIT gene or in a small subset in the constitutively activated at a high level, thereby preventing imatinib PDGFR-alpha gene (2, 3). KIT-activating mutations in GIST are binding. Currently, several drugs, including sunitinib, dasatinib, found predominantly in the juxtamembrane domain of the KIT and sorafenib, are being evaluated for efficacy in the treatment receptor (exon 11) (4), but mutations in the extracellular (exon of imatinib-resistant GIST. Previous in vitro studies indicated 9) and kinase domains of KIT have been described as well (5, 6). The KIT juxtamembrane domain has an autoinhibitory role and stabilizes an inactive conformation of the KIT kinase; mutation of this domain disrupts the conformational integrity and thus KIT Author contributions: B.B., S.D., J.-H.S., G.S., E.d.S., M.A.S.M., C.R.A., and P.B. designed diminishes autoinhibition (7). activation-loop mutations found research; B.B., S.D., F.R., J.-H.S., G.S., J.M.S., and C.R.A. performed research; D.R.V. con- in acute myeloid leukemias, mast cell neoplasms, and seminomas tributed new reagents/analytic tools; B.B., S.D., F.R., J.-H.S., G.S., D.R.V., J.M.S., K.M.-T., stabilize an active conformation of the KIT kinase. M.A.S.M., C.R.A., and P.B. analyzed data; and B.B., S.D., J.M.S., M.A.S.M., C.R.A., and P.B. Imatinib mesylate, an inhibitor of the KIT, PDGFR, and wrote the paper. BCR-ABL tyrosine kinases, is the first-line therapy in patients Conflict of interest statement: P.B. received funding from Novartis for research on GIST. with chronic myelogenous leukemia (CML) and metastatic This article is a PNAS Direct Submission. GIST. Imatinib is most effective in GISTs with KIT-activating Freely available online through the PNAS open access option. mutations in the juxtamembrane domain, some kinase domain 1To whom correspondence should be addressed. E-mail: [email protected]. mutations, or extracellular domain mutations. However, KIT This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. mutations that destabilize the inactive form of the kinase are 1073/pnas.1115240109/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1115240109 PNAS Early Edition | 1of8 Downloaded by guest on September 26, 2021 Δ that both sunitinib and sorafenib inhibit the T670I gatekeeper mice, double-mutant KitV558 ;T669I/+ mice had a prolonged lifespan mutation, but imatinib, dasatinib, and nilotinib failed to do with a median survival of 14 mo (n > 43 each, P < 0.0001) so (17, 18). (Fig. 1B). Δ Because of the clinical importance of imatinib resistance, the Invariably, KitV558 ;T669I/+ mice developed cecal tumors. These Δ development of new strategies for the treatment of GIST is highly tumors were smaller than in KitV558 /+ mice, perhaps explaining relevant. Such strategies may be based on the development of the improved survival by a decreased chance of intestinal ob- KIT kinase inhibitors that show efficacy with the resistant forms struction (Fig. 1C). The average tumor diameter in 3-mo-old Δ Δ of KIT; targeting of downstream signaling components critical animals was fivefold smaller in KitV558 ;T669I/+ than in KitV558 /+ for oncogenic KIT function could provide a second approach. mice (1.4 ± 0.1 mm vs. 7.0 ± 0.3 mm, P < 0.001). Interestingly, However, models to examine these approaches and their possi- not only were the cecal tumors smaller, but the length of the Δ ble side effects in vivo have not been reported. Here we describe cecum was significantly shorter in KitV558 ;T669I/+ mice compared the derivation of a mouse model for imatinib-resistant GIST that V558Δ/+ ± ± V558Δ T669I with Kit and wild-type mice (13 2 mm vs. 24 2 mm, includes both the juxtamembrane domain Kit and Kit P = 0.003) (Fig. 1C). Histological analysis of the shortened Δ gatekeeper mutations as a tool to develop therapeutic strategies cecum of the KitV558 ;T669I/+ mice revealed an intact lumen and Δ for imatinib-resistant GIST and to investigate the consequences mucosa similar to those in KitV558 /+ mice. In contrast to the Δ of KIT oncogenic signaling in other KIT-dependent cell lineages overall reduction in tumor size in the cecum, KitV558 ;T669I/+ mice in particular in hematopoiesis. developed more pronounced ICC hyperplasia in the stomach – V558Δ/+ Results (Fig. 2 C and I; also see Fig. S3Aa d) and colon than Kit Δ mice (Fig. 2 B and H; also see Fig. S3Ba–d). Immunohisto- Derivation and Phenotypic Characterization of KitV558 ;T669I/+ Gate- chemical analysis of gastric and colonic sections revealed KIT keeper Mice. To investigate the consequences of second-site staining as well as phosphorylation of S6, MAPK, and STAT3 KIT mutations on imatinib susceptibility and GIST development V558Δ/+ V558Δ;T669I/+ in vivo, we generated a mouse model introducing both the in the ICC hyperplasia of Kit as well as Kit Δ – – fi KitV558 and the KitT669I gatekeeper mutation, corresponding to mice (see Fig.
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