SYSTEMATIC INVESTIGATION OF DISEASE- AND GENOTYPE-SPECIFIC VULNERABILITIES IN PRIMARY BLOOD CANCER USING HIGH-THROUGHPUT EX VIVO DRUG SCREENING

Abstract

K. D. Hofer and S. Scheinost equally contributing author.

Ex vivo drug screening may leverage the cellular response to drugs for disease understanding, identification of new targets and improved treatment. Precise stratification of patients with hematologic malignancies based on molecular profiling can improve treatment selection and outcome.

Here, we perform a large-scale drug screen across a range of hematologic malignancies to link drug response to diseases and subgroups, identify pathway dependencies and define determinants of drug response. We analyze sequential samples to assess the dynamics of drug response phenotypes over time and compare ex vivo results to clinical outcomes.

For 722 patient samples from 17 blood cancers we assessed drug response to 63 different compounds. The analysis of 143,640 data points shows that drug response is strongly linked to disease entities. We link functional pathway dependencies to individual blood cancers and genetic subgroups. In CLL, trisomy(12) confers susceptibility to inhibition of MEK/ERK and PI3K-AKT-mTOR pathways. DDX3X mutations are associated with increased sensitivity to BTK and SYK inhibition. Longitudinal assessment shows stable drug response over time in untreated patients. Patients receiving BCR signaling inhibitors acquire sensitivities to BET and dual MCL-1/BCL-2 inhibition.

We have generated an accessible resource of ex vivo drug profiling across different hematologic malignancies that can be leveraged for functional analyses and biomarker-stratified treatment strategies.

Research funding declaration: Jacques and Gloria Gossweiler Foundation, Swiss Academy of Medical Sciences, University Hospital Zurich

Keywords: bioinformatics; computational and systems biology; tumor biology and heterogeneity

No potential sources of conflict of interest.