Sorafenib is a potent inhibitor of HP1L1-PDGFRα and the imatinib-resistant FIP1L1-PDGFRα T674I mutant

被引：115

作者：

Lierman, Els

Folens, Cedric

Stover, Elizabeth H.

Mentens, Nicole

Van Miegroet, Helen

Scheers, Werner

Boogaerts, Marc

Vandenberghe, Peter

Marynen, Peter

Cools, Jan

机构：

[1] VIB, Dept Human Genet, Inst Biotechnol, B-3000 Louvain, Belgium

[2] Univ Hosp St Raphael, Dept Hematol, B-3000 Louvain, Belgium

[3] Univ Louvain, Dept Human Genet, B-3001 Louvain, Belgium

[4] Brigham & Womens Hosp, Dept Med, Div Hematol, Boston, MA 02115 USA

[5] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA

来源：

BLOOD | 2006年 / 108卷 / 04期

关键词：

D O I：

10.1182/blood-2006-02-004457

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

The FIP1L1-PDGFRA oncogene is a common cause of chronic eosinophilic leukemia (CEL), and encodes an activated tyrosine kinase that is inhibited by imatinib. FIP1L1-PDGFRA-positive patients with CEL respond to low-dose imatinib therapy, but resistance due to acquired T674I mutation has been observed. We report here the identification of sorafenib as a potent inhibitor of the FIP1 like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFR alpha) (T674I) mutant. Sorafenib inhibited the proliferation of FIP1L1-PDGFR alpha and F1P1L1-PDGFR alpha(T674I)-transformed Ba/F3 cells and induced apoptosis of the EOL-1 cell line at a low nanomolar concentration. Western blot analysis confirmed that these effects were due to a direct effect on FIP1L1-PDGFR alpha and FIP1L1-PDGFR alpha(T674I). Sorafenib was recently approved for the treatment of renal cell carcinoma. Our data suggest that low doses of sorafenib could be efficient for the treatment of FIP1L1-PDGFRA-positive CEL and could be used to overcome resistance to imatinib associated with the T674I mutation.

引用

页码：1374 / 1376

页数：3

共 25 条

[1] Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days on/7 days off in patients with advanced, refractory solid tumours [J].

Awada, A ;

Hendlisz, A ;

Gil, T ;

Bartholomeus, S ;

Mano, M ;

de Valeriola, D ;

Strumberg, D ;

Brendel, E ;

Haase, CG ;

Schwartz, B ;

Piccart, M .

BRITISH JOURNAL OF CANCER, 2005, 92 (10) :1855-1861

[2]

Bain B, 2004, HAEMATOLOGICA, V89, P133

[3] The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA [J].

Baxter, EJ ;

Hochhaus, A ;

Bolufer, P ;

Reiter, A ;

Fernandez, JM ;

Senent, L ;

Cervera, J ;

Moscardo, F ;

Sanz, MA ;

Cross, NCP .

HUMAN MOLECULAR GENETICS, 2002, 11 (12) :1391-1397

[4] Characterization of a conserved structural determinant controlling protein kinase sensitivity to selective inhibitors [J].

Blencke, S ;

Zech, B ;

Engkvist, O ;

Greff, Z ;

Örfi, L ;

Horváth, Z ;

Kéri, G ;

Ullrich, A ;

Daub, H .

CHEMISTRY & BIOLOGY, 2004, 11 (05) :691-701

[5] Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases [J].

Carter, TA ;

Wodicka, LM ;

Shah, NP ;

Velasco, AM ;

Fabian, MA ;

Treiber, DK ;

Milanov, ZV ;

Atteridge, CE ;

Biggs, WH ;

Edeen, PT ;

Floyd, M ;

Ford, JM ;

Grotzfeld, RM ;

Herrgard, S ;

Insko, DE ;

Mehta, SA ;

Patel, HK ;

Pao, W ;

Sawyers, CL ;

Varmus, H ;

Zarrinkar, PP ;

Lockhart, DJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2005, 102 (31) :11011-11016

[6] The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia [J].

Cools, J ;

Quentmeier, H ;

Huntly, BJP ;

Marynen, P ;

Griffin, JD ;

Drexler, HG ;

Gilliland, DG .

BLOOD, 2004, 103 (07) :2802-2805

[7] PKC412 overcomes resistance to imatinib in a murine model of FIP1L1-PDGFRα-induced myeloproliferative disease [J].

Cools, J ;

Stover, EH ;

Boulton, CL ;

Gotlib, J ;

Legare, RD ;

Amaral, SM ;

Curley, DP ;

Duclos, N ;

Rowan, R ;

Kutok, JL ;

Lee, BH ;

Williams, IR ;

Coutre, SE ;

Stone, RM ;

DeAngelo, DJ ;

Marynen, P ;

Manley, PW ;

Meyer, T ;

Fabbro, D ;

Neuberg, D ;

Weisberg, E ;

Griffin, JD ;

Gilliland, DG .

CANCER CELL, 2003, 3 (05) :459-469

[8] Resistance to tyrosine kinase inhibitors: Calling on extra forces [J].

Cools, J ;

Maertens, C ;

Marynen, P .

DRUG RESISTANCE UPDATES, 2005, 8 (03) :119-129

[9] A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome [J].

Cools, J ;

DeAngelo, DJ ;

Gotlib, J ;

Stover, EH ;

Legare, RD ;

Cortes, J ;

Kutok, J ;

Clark, J ;

Galinsky, I ;

Griffin, JD ;

Cross, NCP ;

Tefferi, A ;

Malone, J ;

Alam, R ;

Schrier, SL ;

Schmid, J ;

Rose, M ;

Vandenberghe, P ;

Verhoef, G ;

Boogaerts, M ;

Wlodarska, I ;

Kantarjian, H ;

Marynen, P ;

Coutre, SE ;

Stone, R ;

Gilliland, DG .

NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (13) :1201-1214

[10] A small molecule-kinase interaction map for clinical kinase inhibitors [J].

Fabian, MA ;

Biggs, WH ;

Treiber, DK ;

Atteridge, CE ;

Azimioara, MD ;

Benedetti, MG ;

Carter, TA ;

Ciceri, P ;

Edeen, PT ;

Floyd, M ;

Ford, JM ;

Galvin, M ;

Gerlach, JL ;

Grotzfeld, RM ;

Herrgard, S ;

Insko, DE ;

Insko, MA ;

Lai, AG ;

Lélias, JM ;

Mehta, SA ;

Milanov, ZV ;

Velasco, AM ;

Wodicka, LM ;

Patel, HK ;

Zarrinkar, PP ;

Lockhart, DJ .

NATURE BIOTECHNOLOGY, 2005, 23 (03) :329-336

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