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

Yang, Haitang; Sun, Beibei; Xu, Ke; He, Yunfei; Zhang, Tuo; Hall, Sean; Tan, Swee T; Schmid, Ralph A.; Peng, Ren-Wang; Hu, Guohong; Yao, Feng (2021). Pharmaco-transcriptomic correlation analysis reveals novel responsive signatures to HDAC inhibitors and identifies Dasatinib as a synergistic interactor in small-cell lung cancer. EBioMedicine, 69(103457), p. 103457. Elsevier 10.1016/j.ebiom.2021.103457

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery

UniBE Contributor:

Yang, Haitang; Hall, Sean; Schmid, Ralph and Peng, Ren-Wang

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2352-3964

Publisher:

Elsevier

Language:

English

Submitter:

Thomas Michael Marti

Date Deposited:

27 Jul 2021 15:49

Last Modified:

30 Jul 2021 01:34

Publisher DOI:

10.1016/j.ebiom.2021.103457

PubMed ID:

34224975

Uncontrolled Keywords:

Dasatinib Gene signature Histone deacetylase Isocitrate dehydrogenase Small-cell lung cancer YAP1

BORIS DOI:

10.48350/157714

URI:

https://boris.unibe.ch/id/eprint/157714

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