A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer

被引：478

作者：

Ng, King Pan ^{[2
]}

Hillmer, Axel M. ^{[1
]}

Chuah, Charles T. H. ^{[2
,3
]}

Juan, Wen Chun ^{[2
]}

Ko, Tun Kiat ^{[2
]}

Teo, Audrey S. M. ^{[1
]}

Ariyaratne, Pramila N. ^{[1
]}

Takahashi, Naoto ^{[4
]}

Sawada, Kenichi ^{[4
]}

Fei, Yao ^{[1
,5
]}

Soh, Sheila ^{[2
]}

Lee, Wah Heng ^{[1
]}

Huang, John W. J. ^{[2
]}

Allen, John C., Jr. ^{[6
]}

Woo, Xing Yi ^{[1
]}

Nagarajan, Niranjan ^{[1
]}

Kumar, Vikrant ^{[1
]}

Thalamuthu, Anbupalam ^{[1
]}

Poh, Wan Ting ^{[1
]}

Ang, Ai Leen ^{[3
]}

Mya, Hae Tha ^{[3
]}

How, Gee Fung ^{[3
]}

Yang, Li Yi ^{[3
]}

Koh, Liang Piu ^{[7
]}

Chowbay, Balram ^{[8
]}

Chang, Chia-Tien ^{[2
]}

Nadarajan, Veera S. ^{[9
]}

Chng, Wee Joo ^{[7
,10
,11
]}

Than, Hein ^{[3
]}

Lim, Lay Cheng ^{[3
]}

Goh, Yeow Tee ^{[3
]}

Zhang, Shenli ^{[2
]}

Poh, Dianne ^{[2
]}

Tan, Patrick ^{[1
,2
,11
]}

Seet, Ju-Ee ^{[12
]}

Ang, Mei-Kim ^{[13
]}

Chau, Noan-Minh ^{[13
]}

Ng, Quan-Sing ^{[13
]}

Tan, Daniel S. W. ^{[13
]}

Soda, Manabu

Isobe, Kazutoshi ^{[14
]}

Noethen, Markus M. ^{[15
]}

Wong, Tien Y. ^{[16
]}

Shahab, Atif ^{[1
]}

Ruan, Xiaoan ^{[1
]}

Cacheux-Rataboul, Valere ^{[1
]}

Sung, Wing-Kin ^{[1
]}

Tan, Eng Huat ^{[13
]}

Yatabe, Yasushi

Mano, Hiroyuki ^{[17
]}

机构：

[1] Genome Inst Singapore, Singapore, Singapore

[2] Duke Natl Univ Singapore NUS Grad Med Sch, Canc & Stem Cell Biol Signature Res Programme, Singapore, Singapore

[3] Singapore Gen Hosp, Dept Haematol, Singapore 0316, Singapore

[4] Akita Univ Grad Sch Med, Dept Hematol Nephrol & Rheumatol, Akita, Japan

[5] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Epidemiol & Publ Hlth, Singapore 117595, Singapore

[6] Duke NUS Grad Med Sch, Ctr Quantitat Med, Singapore, Singapore

[7] Natl Univ Hlth Syst, Natl Univ Canc Inst Singapore, Dept Hematol Oncol, Singapore, Singapore

[8] Natl Canc Ctr, Clin Pharmacol Lab, Singapore, Singapore

[9] Univ Malaya, Kuala Lumpur, Malaysia

[10] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore 117595, Singapore

[11] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore

[12] Natl Univ Hlth Syst, Dept Pathol, Singapore, Singapore

[13] Natl Canc Ctr, Dept Med Oncol, Singapore, Singapore

[14] Toho Univ Omori Med Ctr, Dept Resp Med, Tokyo, Japan

[15] Univ Bonn, Inst Human Genet, Bonn, Germany

[16] Singapore Natl Eye Ctr, Singapore Eye Res Inst, Singapore, Singapore

[17] Univ Tokyo, Grad Sch Med, Dept Med Genom, Tokyo, Japan

[18] Duke NUS Grad Med Sch, Off Clin Sci, Singapore, Singapore

[19] Natl Univ Singapore, Dept Biochem, Singapore 117548, Singapore

[20] Duke Univ Med Ctr, Div Med Oncol, Dept Med, Durham, NC USA

来源：

NATURE MEDICINE | 2012年 / 18卷 / 04期

基金：

英国医学研究理事会;

关键词：

CHRONIC MYELOID-LEUKEMIA; CELL LUNG-CANCER; FACTOR RECEPTOR EGFR; EYE DISEASES; GROWTH; MUTATIONS; GEFITINIB; APOPTOSIS; RESPONSIVENESS; IDENTIFICATION;

D O I：

10.1038/nm.2713

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Tyrosine kinase inhibitors (TKIs) elicit high response rates among individuals with kinase-driven malignancies, including chronic myeloid leukemia (CML) and epidermal growth factor receptor-mutated non-small-cell lung cancer (EGFR NSCLC). However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. Using paired-end DNA sequencing, we discovered a common intronic deletion polymorphism in the gene encoding BCL2-like 11 (BIM). BIM is a pro-apoptotic member of the B-cell CLL/lymphoma 2 (BCL2) family of proteins, and its upregulation is required for TKIs to induce apoptosis in kinase-driven cancers. The polymorphism switched BIM splicing from exon 4 to exon 3, which resulted in expression of BIM isoforms lacking the pro-apoptotic BCL2-homology domain 3 (BH3). The polymorphism was sufficient to confer intrinsic TKI resistance in CML and EGFR NSCLC cell lines, but this resistance could be overcome with BH3-mimetic drugs. Notably, individuals with CML and EGFR NSCLC harboring the polymorphism experienced significantly inferior responses to TKIs than did individuals without the polymorphism (P = 0.02 for CML and P = 0.027 for EGFR NSCLC). Our results offer an explanation for the heterogeneity of TKI responses across individuals and suggest the possibility of personalizing therapy with BH3 mimetics to overcome BIM-polymorphism-associated TKI resistance.

引用

页码：521 / 528

页数：8

共 53 条

[1] Nomenclature of dynein light chain-linked BH3-only protein Bim isoforms [J].

Adachi, M ;

Zhao, X ;

Imai, K .

CELL DEATH AND DIFFERENTIATION, 2005, 12 (02) :192-193

[2] Low-level expression of proapoptotic Bcl-2-interacting mediator in leukemic cells in patients with chronic myeloid leukemia: Role of BCR/ABL, characterization of underlying signaling pathways, and reexpression by novel pharmacologic compounds [J].

Aichberger, KJ ;

Mayerhofer, M ;

Krauth, MT ;

Vales, A ;

Kondo, R ;

Derdak, S ;

Pickl, WF ;

Selzer, E ;

Deininger, M ;

Druker, BJ ;

Sillaber, C ;

Esterbauer, H ;

Valent, P .

CANCER RESEARCH, 2005, 65 (20) :9436-9444

[3] Chronic myeloid leukemia in Asia [J].

Au, Wing Y. ;

Caguioa, Priscilla B. ;

Chuah, Charles ;

Hsu, Szu Chun ;

Jootar, Saengsuree ;

Kim, Dong-Wook ;

Kweon, Il-Young ;

O'Neil, William M. ;

Saikia, Tapan K. ;

Wang, Jianxiang .

INTERNATIONAL JOURNAL OF HEMATOLOGY, 2009, 89 (01) :14-23

[4] Chronic Myeloid Leukemia: An Update of Concepts and Management Recommendations of European LeukemiaNet [J].

Baccarani, Michele ;

Cortes, Jorge ;

Pane, Fabrizio ;

Niederwieser, Dietger ;

Saglio, Giuseppe ;

Apperley, Jane ;

Cervantes, Francisco ;

Deininger, Michael ;

Gratwohl, Alois ;

Guilhot, Francois ;

Hochhaus, Andreas ;

Horowitz, Mary ;

Hughes, Timothy ;

Kantarjian, Hagop ;

Larson, Richard ;

Radich, Jerald ;

Simonsson, Bengt ;

Silver, Richard T. ;

Goldman, John ;

Hehlmann, Rudiger .

JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (35) :6041-6051

[5] FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR [J].

Bivona, Trever G. ;

Hieronymus, Haley ;

Parker, Joel ;

Chang, Kenneth ;

Taron, Miquel ;

Rosell, Rafael ;

Moonsamy, Philicia ;

Dahlman, Kimberly ;

Miller, Vincent A. ;

Costa, Carlota ;

Hannon, Gregory ;

Sawyers, Charles L. .

NATURE, 2011, 471 (7339) :523-526

[6]

Carella AM, 1997, HAEMATOLOGICA, V82, P478

[7] An intronic sequence element mediates both activation and repression of rat fibroblast growth factor receptor 2 pre-mRNA splicing [J].

Carstens, RP ;

McKeehan, WL ;

Garcia-Blanco, MA .

MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (04) :2205-2217

[8] Listening to silence and understanding nonsense: Exonic mutations that affect splicing [J].

Cartegni, L ;

Chew, SL ;

Krainer, AR .

NATURE REVIEWS GENETICS, 2002, 3 (04) :285-298

[9] BCL-2, BCL-XL sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis [J].

Cheng, EHYA ;

Wei, MC ;

Weiler, S ;

Flavell, RA ;

Mak, TW ;

Lindsten, T ;

Korsmeyer, SJ .

MOLECULAR CELL, 2001, 8 (03) :705-711

[10] BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations [J].

Costa, Daniel B. ;

Halmos, Balazs ;

Kumar, Amit ;

Schumer, Susan T. ;

Huberman, Mark S. ;

Boggon, Titus J. ;

Tenen, Daniel G. ;

Kobayashi, Susumu .

PLOS MEDICINE, 2007, 4 (10) :1669-1680

← 1 2 3 4 5 6 →