Systematic Mapping Of Drug and Pathway Sensitivity In Chronic Lymphocytic Leukemia Identifies Synthetic Lethal Interactions Of Mutant p53
Sellner L, Malgorzata O, Slabicki M et al.




Key Points:
  • Primary CLL cells characterized with ex vivo high-throughput drug screening platform.

  • Drug library consisted of 67 compounds at different concentrations.

  • Micro-environmental conditions mimicked by heat inactivated human serum.

  • CLL samples: untreated, sensitive or refractory disease and major genetic subgroups.

  • Cell viability assessed 48 and 72 hours after drug application.

  • Drug sensitivity regressed on genetic profiles.

  • Results reported from 97 primary CLL samples.

  • Nutlin-3a and fludarabine: induced cell death with wild-type p53 (n=80) but considerably less in CLL with mutated p53.

  • Inhibitors with related targets showed similar response profiles across patients.

  • Drug effects can be based on functional and genetic properties of tumors.

Implications:

  • First comprehensive data map of genetically determined drug sensitivity in CLL.
Additional Comments:
  • CLL functional classification based on drug sensitivity.

  • TP53 mutant CLL: identifies synthetic lethal interaction.


View the original abstract on the ASH website.






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