Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL.
Nat Chem Biol
; 15(3): 232-240, 2019 03.
Article
en En
| MEDLINE
| ID: mdl-30692684
ABSTRACT
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Leucemia Linfocítica Crónica de Células B
/
Agammaglobulinemia Tirosina Quinasa
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Año:
2019
Tipo del documento:
Article