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Drug-microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL

Peter-Martin Bruch1,2, Holly Ar Giles1,2,3,4, Carolin Kolb1,2

  • 1Department of Medicine V, Heidelberg University Hospital, Heidelberg, Germany.

Molecular Systems Biology
|August 12, 2022
PubMed

Insights

The tumor microenvironment significantly impacts cancer drug effectiveness. Researchers found specific microenvironmental stimuli and genetic changes, like trisomy 12, alter chronic lymphocytic leukemia (CLL) drug responses, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Cancer Biology
  • Immunology

Background:

  • The tumor microenvironment (TME) and genetic alterations critically influence cancer drug efficacy.
  • Limited systematic analyses exist on the interplay between TME stimuli and drug response in genetically diverse cancers.
  • Chronic lymphocytic leukemia (CLL) serves as a model to dissect these complex interactions.

Purpose of the Study:

  • To investigate the impact of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterized CLL patient samples.
  • To identify subgroups based on TME response and their clinical outcomes.
  • To explore the role of trisomy 12 in TME-mediated drug resistance and epigenetic modifications.

Main Methods:

  • Systematic analysis of 17 microenvironmental stimuli across 12 drugs in 192 CLL patient samples.
  • Genomic characterization of patient samples to correlate genetic alterations with drug response.
  • Epigenetic profiling and assessment of bromodomain inhibition efficacy.
  • Quantification of interleukin 4 (IL4) and Toll-like receptor (TLR) signaling activity in patient samples and lymph nodes.

Main Results:

  • Four distinct patient subgroups with varying clinical outcomes were identified based on TME response, independent of known prognostic markers.
  • Trisomy 12 samples exhibited amplified responses to microenvironmental stimuli and a unique epigenetic signature.
  • Bromodomain inhibition reversed the epigenetic profile in trisomy 12 CLL and targeted TME signaling.
  • IL4 and TLR stimulation were identified as key drivers of drug resistance, with increased activity in CLL lymph nodes and IL4 activity correlating with faster disease progression.

Conclusions:

  • The TME and genetic factors significantly modulate drug response in CLL, defining distinct clinical subgroups.
  • Trisomy 12 confers sensitivity to TME influences and suggests a therapeutic window for bromodomain inhibitors.
  • IL4 and TLR signaling are critical mediators of drug resistance in CLL, offering potential therapeutic targets.
Keywords:
chronic lymphocytic leukaemiadrug perturbationmicroenvironmentmulti-omicstrisomy 12

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