Crizotinib-Resistant NPM-ALK Mutants Confer Differential Sensitivity to Unrelated Alk Inhibitors

被引:73
作者
Ceccon, Monica [1 ]
Mologni, Luca [1 ]
Bisson, William [3 ]
Scapozza, Leonardo [3 ]
Gambacorti-Passerini, Carlo [1 ,2 ]
机构
[1] Univ Milano Bicocca, Dept Hlth Sci, I-20900 Monza, Italy
[2] San Gerardo Hosp, Sect Haematol, Monza, Italy
[3] Univ Geneva, Sect Sci Pharmaceut, Geneva, Switzerland
关键词
ANAPLASTIC LYMPHOMA KINASE; LUNG-CANCER; ACTIVATING MUTATIONS; ONCOGENIC MUTATIONS; PROTEIN; GENE; FUSION; IDENTIFICATION; MUTAGENESIS; EXPRESSION;
D O I
10.1158/1541-7786.MCR-12-0569
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The dual ALK/MET inhibitor crizotinib was recently approved for the treatment of metastatic and late-stage ALK+ NSCLC, and is currently in clinical trial for other ALK-related diseases. As predicted after other tyrosine kinase inhibitors' clinical experience, the first mutations that confer resistance to crizotinib have been described in patients with non-small cell lung cancer (NSCLC) and in one patient inflammatory myofibroblastic tumor (IMT). Here, we focused our attention on the anaplastic large cell lymphoma (ALCL), where the oncogenic fusion protein NPM-ALK, responsible for 70% to 80% of cases, represents an ideal crizotinib target. We selected and characterized 2 human NPM-ALK+ ALCL cell lines, KARPAS-299 and SUP-M2, able to survive and proliferate at different crizotinib concentrations. Sequencing of ALK kinase domain revealed that a single mutation became predominant at high crizotinib doses in each cell line, namely L1196Q and I1171N in Karpas-299 and SUP-M2 cells, respectively. These mutations also conferred resistance to crizotinib in Ba/F3 cells expressing human NPM-ALK. The resistant cell populations, as well as mutated Ba/F3 cells, were characterized for sensitivity to two additional ALK inhibitors: the dual ALK/EGFR inhibitor AP26113 and NVP-TAE684. While L1196Q-positive cell lines were sensitive to both inhibitors, cells carrying I1171N substitution showed cross-resistance to all ALK inhibitors tested. This study provides potentially relevant information for the management of patients with ALCL that may relapse after crizotinib treatment. Mol Cancer Res; 11(2); 122-32. (c) 2012 AACR.
引用
收藏
页码:122 / 132
页数:11
相关论文
共 47 条
  • [1] [Anonymous], CANC RES S
  • [2] Role of the nucleophosmin (NPM) portion of the non-Hodgkin's lymphoma-associated NPM-anaplastic lymphoma kinase fusion protein in oncogenesis
    Bischof, D
    Pulford, K
    Mason, DY
    Morris, SW
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (04) : 2312 - 2325
  • [3] MAJOR NUCLEOLAR PROTEINS SHUTTLE BETWEEN NUCLEUS AND CYTOPLASM
    BORER, RA
    LEHNER, CF
    EPPENBERGER, HM
    NIGG, EA
    [J]. CELL, 1989, 56 (03) : 379 - 390
  • [4] Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors
    Bossi, Roberto T.
    Saccardo, M. Beatrice
    Ardini, Elena
    Menichincheri, Maria
    Rusconi, Luisa
    Magnaghi, Paola
    Orsini, Paolo
    Avanzi, Nilla
    Borgia, Andrea Lombardi
    Nesi, Marcella
    Bandiera, Tiziano
    Fogliatto, Gianpaolo
    Bertrand, Jay A.
    [J]. BIOCHEMISTRY, 2010, 49 (32) : 6813 - 6825
  • [5] Oncogenic mutations of ALK kinase in neuroblastoma
    Chen, Yuyan
    Takita, Junko
    Choi, Young Lim
    Kato, Motohiro
    Ohira, Miki
    Sanada, Masashi
    Wang, Lili
    Soda, Manabu
    Kikuchi, Akira
    Igarashi, Takashi
    Nakagawara, Akira
    Hayashi, Yasuhide
    Mano, Hiroyuki
    Ogawa, Seishi
    [J]. NATURE, 2008, 455 (7215) : 971 - U56
  • [6] Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target
    Chiarle, R
    Simmons, WJ
    Cai, HY
    Dhall, G
    Zamo', A
    Raz, R
    Karras, JG
    Levy, DE
    Inghirami, G
    [J]. NATURE MEDICINE, 2005, 11 (06) : 623 - 629
  • [7] The anaplastic lymphoma kinase in the pathogenesis of cancer
    Chiarle, Roberto
    Voena, Claudia
    Ambrogio, Chiara
    Piva, Roberto
    Inghirami, Giorgio
    [J]. NATURE REVIEWS CANCER, 2008, 8 (01) : 11 - 23
  • [8] EML4-ALK Mutations in Lung Cancer That Confer Resistance to ALK Inhibitors
    Choi, Young Lim
    Soda, Manabu
    Yamashita, Yoshihiro
    Ueno, Toshihide
    Takashima, Junpei
    Nakajima, Takahiro
    Yatabe, Yasushi
    Takeuchi, Kengo
    Hamada, Toru
    Haruta, Hidenori
    Ishikawa, Yuichi
    Kimura, Hideki
    Mitsudomi, Tetsuya
    Tanio, Yoshiro
    Mano, Hiroyuki
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (18) : 1734 - 1739
  • [9] CSF Concentration of the Anaplastic Lymphoma Kinase Inhibitor Crizotinib
    Costa, Daniel B.
    Kobayashi, Susumu
    Pandya, Shuchi S.
    Yeo, Wee-Lee
    Shen, Zhongzhou
    Tan, Weiwei
    Wilner, Keith D.
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (15) : E443 - E445
  • [10] Structure Based Drug Design of Crizotinib (PF-02341066), a Potent and Selective Dual Inhibitor of Mesenchymal-Epithelial Transition Factor (c-MET) Kinase and Anaplastic Lymphoma Kinase (ALK)
    Cui, J. Jean
    Tran-Dube, Michelle
    Shen, Hong
    Nambu, Mitchell
    Kung, Pei-Pei
    Pairish, Mason
    Jia, Lei
    Meng, Jerry
    Funk, Lee
    Botrous, Iriny
    McTigue, Michele
    Grodsky, Neil
    Ryan, Kevin
    Padrique, Ellen
    Alton, Gordon
    Timofeevski, Sergei
    Yamazaki, Shinji
    Li, Quhua
    Zou, Helen
    Christensen, James
    Mroczkowski, Barbara
    Bender, Steve
    Kania, Robert S.
    Edwards, Martin P.
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (18) : 6342 - 6363