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

Nat Med. 2012 Mar 18;18(4):521-8. doi: 10.1038/nm.2713.

Abstract

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.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Annexins / metabolism
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / genetics*
  • BH3 Interacting Domain Death Agonist Protein / genetics
  • Bcl-2-Like Protein 11
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Cell Line, Tumor
  • Cohort Studies
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Enzyme-Linked Immunosorbent Assay / methods
  • ErbB Receptors / genetics
  • Exons / genetics
  • Female
  • Follow-Up Studies
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Frequency
  • Genotype
  • Humans
  • International Cooperation
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics*
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Polymorphism, Genetic / genetics*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins / genetics*
  • RNA, Small Interfering / metabolism
  • Sequence Deletion / genetics*
  • Statistics, Nonparametric
  • Transfection

Substances

  • Annexins
  • Apoptosis Regulatory Proteins
  • BCL2L11 protein, human
  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Bcl-2-Like Protein 11
  • Membrane Proteins
  • Protein Isoforms
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • ErbB Receptors

Associated data

  • GEO/GSE26954
  • GEO/GSE28303