PMID- 22426421
OWN - NLM
STAT- MEDLINE
DCOM- 20120607
LR  - 20221222
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Linking)
VI  - 18
IP  - 4
DP  - 2012 Mar 18
TI  - A common BIM deletion polymorphism mediates intrinsic resistance and inferior 
      responses to tyrosine kinase inhibitors in cancer.
PG  - 521-8
LID - 10.1038/nm.2713 [doi]
AB  - 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.
FAU - Ng, King Pan
AU  - Ng KP
AD  - Cancer & Stem Cell Biology Signature Research Programme, Duke-National University 
      of Singapore Graduate Medical School, Singapore.
FAU - Hillmer, Axel M
AU  - Hillmer AM
FAU - Chuah, Charles T H
AU  - Chuah CT
FAU - Juan, Wen Chun
AU  - Juan WC
FAU - Ko, Tun Kiat
AU  - Ko TK
FAU - Teo, Audrey S M
AU  - Teo AS
FAU - Ariyaratne, Pramila N
AU  - Ariyaratne PN
FAU - Takahashi, Naoto
AU  - Takahashi N
FAU - Sawada, Kenichi
AU  - Sawada K
FAU - Fei, Yao
AU  - Fei Y
FAU - Soh, Sheila
AU  - Soh S
FAU - Lee, Wah Heng
AU  - Lee WH
FAU - Huang, John W J
AU  - Huang JW
FAU - Allen, John C Jr
AU  - Allen JC Jr
FAU - Woo, Xing Yi
AU  - Woo XY
FAU - Nagarajan, Niranjan
AU  - Nagarajan N
FAU - Kumar, Vikrant
AU  - Kumar V
FAU - Thalamuthu, Anbupalam
AU  - Thalamuthu A
FAU - Poh, Wan Ting
AU  - Poh WT
FAU - Ang, Ai Leen
AU  - Ang AL
FAU - Mya, Hae Tha
AU  - Mya HT
FAU - How, Gee Fung
AU  - How GF
FAU - Yang, Li Yi
AU  - Yang LY
FAU - Koh, Liang Piu
AU  - Koh LP
FAU - Chowbay, Balram
AU  - Chowbay B
FAU - Chang, Chia-Tien
AU  - Chang CT
FAU - Nadarajan, Veera S
AU  - Nadarajan VS
FAU - Chng, Wee Joo
AU  - Chng WJ
FAU - Than, Hein
AU  - Than H
FAU - Lim, Lay Cheng
AU  - Lim LC
FAU - Goh, Yeow Tee
AU  - Goh YT
FAU - Zhang, Shenli
AU  - Zhang S
FAU - Poh, Dianne
AU  - Poh D
FAU - Tan, Patrick
AU  - Tan P
FAU - Seet, Ju-Ee
AU  - Seet JE
FAU - Ang, Mei-Kim
AU  - Ang MK
FAU - Chau, Noan-Minh
AU  - Chau NM
FAU - Ng, Quan-Sing
AU  - Ng QS
FAU - Tan, Daniel S W
AU  - Tan DS
FAU - Soda, Manabu
AU  - Soda M
FAU - Isobe, Kazutoshi
AU  - Isobe K
FAU - Nothen, Markus M
AU  - Nothen MM
FAU - Wong, Tien Y
AU  - Wong TY
FAU - Shahab, Atif
AU  - Shahab A
FAU - Ruan, Xiaoan
AU  - Ruan X
FAU - Cacheux-Rataboul, Valere
AU  - Cacheux-Rataboul V
FAU - Sung, Wing-Kin
AU  - Sung WK
FAU - Tan, Eng Huat
AU  - Tan EH
FAU - Yatabe, Yasushi
AU  - Yatabe Y
FAU - Mano, Hiroyuki
AU  - Mano H
FAU - Soo, Ross A
AU  - Soo RA
FAU - Chin, Tan Min
AU  - Chin TM
FAU - Lim, Wan-Teck
AU  - Lim WT
FAU - Ruan, Yijun
AU  - Ruan Y
FAU - Ong, S Tiong
AU  - Ong ST
LA  - eng
SI  - GEO/GSE26954
SI  - GEO/GSE28303
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20120318
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Annexins)
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (BCL2L11 protein, human)
RN  - 0 (BH3 Interacting Domain Death Agonist Protein)
RN  - 0 (BID protein, human)
RN  - 0 (Bcl-2-Like Protein 11)
RN  - 0 (Membrane Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
CIN - Nat Rev Clin Oncol. 2012 Apr 10;9(5):247. doi: 10.1038/nrclinonc.2012.57. PMID: 
      22473101
CIN - Nat Med. 2012 Apr 05;18(4):494-6. doi: 10.1038/nm.2725. PMID: 22481406
CIN - Nat Med. 2014 Oct;20(10):1090. doi: 10.1038/nm.3638. PMID: 25295932
CIN - Nat Med. 2014 Oct;20(10):1090-1. doi: 10.1038/nm.3652. PMID: 25295933
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Annexins/metabolism
MH  - Apoptosis/*drug effects
MH  - Apoptosis Regulatory Proteins/*genetics
MH  - BH3 Interacting Domain Death Agonist Protein/genetics
MH  - Bcl-2-Like Protein 11
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/*genetics
MH  - Cell Line, Tumor
MH  - Cohort Studies
MH  - Dose-Response Relationship, Drug
MH  - Drug Resistance, Neoplasm/*drug effects/genetics
MH  - Enzyme-Linked Immunosorbent Assay/methods
MH  - ErbB Receptors/genetics
MH  - Exons/genetics
MH  - Female
MH  - Follow-Up Studies
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Gene Frequency
MH  - Genotype
MH  - Humans
MH  - International Cooperation
MH  - Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy/*genetics
MH  - Lung Neoplasms/drug therapy/*genetics
MH  - Male
MH  - Membrane Proteins/*genetics
MH  - Middle Aged
MH  - Polymorphism, Genetic/*genetics
MH  - Protein Isoforms/genetics/metabolism
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins/*genetics
MH  - RNA, Small Interfering/metabolism
MH  - Sequence Deletion/*genetics
MH  - Statistics, Nonparametric
MH  - Transfection
EDAT- 2012/03/20 06:00
MHDA- 2012/06/08 06:00
CRDT- 2012/03/20 06:00
PHST- 2011/09/07 00:00 [received]
PHST- 2012/02/21 00:00 [accepted]
PHST- 2012/03/20 06:00 [entrez]
PHST- 2012/03/20 06:00 [pubmed]
PHST- 2012/06/08 06:00 [medline]
AID - nm.2713 [pii]
AID - 10.1038/nm.2713 [doi]
PST - epublish
SO  - Nat Med. 2012 Mar 18;18(4):521-8. doi: 10.1038/nm.2713.