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

Autor: Naoto Takahashi, V. S. Nadarajan, Yijun Ruan, Anbupalam Thalamuthu, Wing-Kin Sung, Xing Yi Woo, Hae Tha Mya, Sheila Soh, Xiaoan Ruan, Wen Chun Juan, Kazutoshi Isobe, Markus M. Nöthen, Wan-Teck Lim, John W.J. Huang, Hein Than, Yao Fei, L.Y. Yang, Chia-Tien Chang, Dianne Poh, Noan-Minh Chau, Axel M. Hillmer, Liang Piu Koh, Ai Leen Ang, Gee Fung How, Mei-Kim Ang, Yeow Tee Goh, Lay Cheng Lim, Tan Min Chin, Daniel Shao-Weng Tan, Wee Joo Chng, Balram Chowbay, Audrey S.M. Teo, Hiroyuki Mano, Ju Ee Seet, Niranjan Nagarajan, Quan Sing Ng, Shenli Zhang, Pramila N. Ariyaratne, Atif Shahab, Wan Ting Poh, Manabu Soda, Patrick Tan, Yasushi Yatabe, Kenichi Sawada, Vikrant Kumar, Ross A. Soo, Tien Yin Wong, Valere Cacheux-Rataboul, Charles Chuah, Eng Huat Tan, John Carson Allen, King Pan Ng, Wah Heng Lee, S. Tiong Ong, Tun Kiat Ko
Rok vydání: 2011
Předmět:
Male
Lung Neoplasms
International Cooperation
Apoptosis
Cohort Studies
Exon
Gene Frequency
Epidermal growth factor
hemic and lymphatic diseases
Carcinoma
Non-Small-Cell Lung
Genotype
Protein Isoforms
RNA
Small Interfering
Sequence Deletion
Aged
80 and over
Bcl-2-Like Protein 11
Myeloid leukemia
General Medicine
Exons
Middle Aged
ErbB Receptors
Gene Expression Regulation
Neoplastic
Leukemia
Female
biological phenomena
cell phenomena
and immunity
Tyrosine kinase
BH3 Interacting Domain Death Agonist Protein
Adult
Annexins
Enzyme-Linked Immunosorbent Assay
Biology
Transfection
General Biochemistry
Genetics and Molecular Biology
Statistics
Nonparametric
Cell Line
Tumor
Leukemia
Myelogenous
Chronic
BCR-ABL Positive
Proto-Oncogene Proteins
medicine
Humans
Lung cancer
neoplasms
Protein Kinase Inhibitors
Aged
Polymorphism
Genetic
Dose-Response Relationship
Drug
Membrane Proteins
medicine.disease
respiratory tract diseases
BCL2L11
Drug Resistance
Neoplasm
Immunology
Cancer research
Apoptosis Regulatory Proteins
Follow-Up Studies
Zdroj: Nature medicine. 18(4)
ISSN: 1546-170X
Popis: 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.
Databáze: OpenAIRE
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