Gene isoforms as expression-based biomarkers predictive of drug response in vitro

Nat Commun. 2017 Oct 24;8(1):1126. doi: 10.1038/s41467-017-01153-8.

Abstract

Next-generation sequencing technologies have recently been used in pharmacogenomic studies to characterize large panels of cancer cell lines at the genomic and transcriptomic levels. Among these technologies, RNA-sequencing enable profiling of alternatively spliced transcripts. Given the high frequency of mRNA splicing in cancers, linking this feature to drug response will open new avenues of research in biomarker discovery. To identify robust transcriptomic biomarkers for drug response across studies, we develop a meta-analytical framework combining the pharmacological data from two large-scale drug screening datasets. We use an independent pan-cancer pharmacogenomic dataset to test the robustness of our candidate biomarkers across multiple cancer types. We further analyze two independent breast cancer datasets and find that specific isoforms of IGF2BP2, NECTIN4, ITGB6, and KLHDC9 are significantly associated with AZD6244, lapatinib, erlotinib, and paclitaxel, respectively. Our results support isoform expressions as a rich resource for biomarkers predictive of drug response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Antineoplastic Agents / pharmacology
  • Benzimidazoles / pharmacology
  • Biomarkers / metabolism*
  • Breast Neoplasms / genetics
  • Carrier Proteins / genetics
  • Cell Adhesion Molecules / genetics
  • Chemistry, Pharmaceutical
  • Drug Screening Assays, Antitumor*
  • Erlotinib Hydrochloride / pharmacology
  • Genome, Human
  • Humans
  • Integrin beta Chains / genetics
  • Lapatinib
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Paclitaxel / pharmacology
  • Pharmacogenetics*
  • Protein Isoforms / genetics*
  • Quinazolines / pharmacology
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / genetics
  • Sequence Analysis, RNA
  • Transcriptome

Substances

  • AZD 6244
  • Antineoplastic Agents
  • Benzimidazoles
  • Biomarkers
  • Carrier Proteins
  • Cell Adhesion Molecules
  • IGF2BP2 protein, human
  • Integrin beta Chains
  • KLHDC9 protein, human
  • Protein Isoforms
  • Quinazolines
  • RNA, Messenger
  • RNA-Binding Proteins
  • integrin beta6
  • NECTIN4 protein, human
  • Lapatinib
  • Erlotinib Hydrochloride
  • Paclitaxel

Grants and funding