The Neuroblastoma-Associated F1174L ALK Mutation Causes Resistance to an ALK Kinase Inhibitor in ALK-Translocated Cancers

被引：255

作者：

Sasaki, Takaaki ^{[1
,2
]}

Okuda, Katsuhiro ^{[1
,2
]}

Zheng, Wei ^{[3
,4
]}

Butrynski, James ^{[2
,5
]}

Capelletti, Marzia ^{[1
,2
]}

Wang, Liping ^{[1
,2
]}

Gray, Nathanael S. ^{[3
,4
]}

Wilner, Keith ^{[6
]}

Christensen, James G. ^{[6
]}

Demetri, George ^{[2
,5
]}

Shapiro, Geoffrey I. ^{[1
,2
,7
,9
]}

Rodig, Scott J. ^{[8
]}

Eck, Michael J. ^{[3
,4
]}

Jaenne, Pasi A. ^{[1
,2
,9
]}

机构：

[1] Dana Farber Canc Inst, Lowe Ctr Thorac Oncol, Boston, MA 02115 USA

[2] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Dana Farber Canc Inst, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[5] Dana Farber Canc Inst, Ctr Sarcoma & Bone Oncol, Boston, MA 02115 USA

[6] Pfizer Global Res & Dev, Dept Res Pharmacol, La Jolla, CA USA

[7] Dana Farber Canc Inst, Early Drug Dev Ctr, Boston, MA 02115 USA

[8] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[9] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

来源：

CANCER RESEARCH | 2010年 / 70卷 / 24期

关键词：

ANAPLASTIC LYMPHOMA KINASE; EML4-ALK FUSION GENE; CHRONIC-PHASE; C-MET; LUNG; IDENTIFICATION; IMATINIB; NPM;

D O I：

10.1158/0008-5472.CAN-10-2956

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harboring a RANBP2-ALK translocation who progressed while on crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth, and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib-mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, and the HSP90 inhibitor 17-AAG are both effective in models harboring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers. Cancer Res; 70(24); 10038-43. (C) 2010 AACR.

引用

页码：10038 / 10043

页数：6

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