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

The tumour microenvironment and genetic alterations collectively influence drug efficacy in cancer, but current evidence is limited and systematic analyses are lacking. Using chronic lymphocytic leukaemia (CLL) as a model disease, we investigated the influence of 17 microenvironmental stimuli on 12 drugs in 192 genetically characterised patient samples. Based on microenvironmental response, we identified four subgroups with distinct clinical outcomes beyond known prognostic markers. Response to multiple microenvironmental stimuli was amplified in trisomy 12 samples. Trisomy 12 was associated with a distinct epigenetic signature. Bromodomain inhibition reversed this epigenetic profile and could be used to target microenvironmental signalling in trisomy 12 CLL. We quantified the impact of microenvironmental stimuli on drug response and their dependence on genetic alterations, identifying interleukin 4 (IL4) and Toll-like receptor (TLR) stimulation as the strongest actuators of drug resistance. IL4 and TLR signalling activity was increased in CLL-infiltrated lymph nodes compared with healthy samples. High IL4 activity correlated with faster disease progression. The publicly available dataset can facilitate the investigation of cell-extrinsic mechanisms of drug resistance and disease progression.

Automated summary

The tumor microenvironment and genetic alterations play a collective role in influencing the efficacy of cancer drugs. This study investigated the impact of microenvironmental stimuli on drug response in chronic lymphocytic leukemia (CLL) patients and identified distinct subgroups with different clinical outcomes. The researchers also found that trisomy 12 samples exhibited amplified response to multiple microenvironmental stimuli and had a unique epigenetic signature. Additionally, interleukin 4 (IL4) and Toll-like receptor (TLR) signaling were identified as strong contributors to drug resistance. The findings highlight the importance of considering both microenvironmental factors and genetic alterations in cancer treatment.