Pharmaco-transcriptomic correlation analysis reveals novel responsive signatures to HDAC inhibitors and identifies Dasatinib as a synergistic interactor in small-cell lung cancer

EBioMedicine. 2021 Jul:69:103457. doi: 10.1016/j.ebiom.2021.103457. Epub 2021 Jul 3.

Abstract

Background: Histone acetylation/deacetylase process is one of the most studied epigenetic modifications. Histone deacetylase inhibitors (HDACis) have shown clinical benefits in haematological malignancies but failed in solid tumours due to the lack of biomarker-driven stratification.

Methods: We perform integrative pharmaco-transcriptomic analysis by correlating drug response profiles of five pan-HDACis with transcriptomes of solid cancer cell lines (n=659) to systematically identify generalizable gene signatures associated with HDACis sensitivity and resistance. The established signatures are then applied to identify cancer subtypes that are potentially sensitive or resistant to HDACis, and drugs that enhance the efficacy of HDACis. Finally, the reproductivity of the established HDACis signatures is evaluated by multiple independent drug response datasets and experimental assays.

Findings: We successfully delineate generalizable gene signatures predicting sensitivity (containing 46 genes) and resistance (containing 53 genes) to all five HDACis, with their reproductivity confirmed by multiple external sources and independent internal assays. Using the gene signatures, we identify low-grade glioma harbouring isocitrate dehydrogenase 1/2 (IDH1/2) mutation and non-YAP1-driven subsets of small-cell lung cancer (SCLC) that particularly benefit from HDACis monotherapy. Further, based on the resistance gene signature, we identify clinically-approved Dasatinib as a synthetic lethal drug with HDACi, synergizing in inducing apoptosis and reactive oxygen species on a panel of SCLC. Finally, Dasatinib significantly enhances the therapeutic efficacy of Vorinostat in SCLC xenografts.

Interpretation: Our work establishes robust gene signatures predicting HDACis sensitivity/resistance in solid cancer and uncovers combined Dasatinib/HDACi as a synthetic lethal combination therapy for SCLC.

Funding: This work was supported by the National Natural Science Foundation of China (82072570 to F. Yao; 82002941 to B. Sun).

Keywords: Dasatinib; Gene signature; Histone deacetylase; Isocitrate dehydrogenase; Small-cell lung cancer; YAP1.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Cell Line, Tumor
  • Dasatinib / administration & dosage
  • Dasatinib / therapeutic use*
  • Drug Resistance, Neoplasm*
  • Drug Synergism
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Humans
  • Isocitrate Dehydrogenase / genetics
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutation
  • Pharmacogenomic Variants
  • Transcription Factors / genetics
  • Transcriptome*
  • Vorinostat / administration & dosage
  • Vorinostat / therapeutic use
  • YAP-Signaling Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • Transcription Factors
  • YAP-Signaling Proteins
  • YAP1 protein, human
  • Vorinostat
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • Dasatinib