High-throughput profiling of signaling networks identifies mechanism-based combination therapy to eliminate microenvironmental resistance in acute myeloid leukemia.

摘要: The bone marrow microenvironment is known to provide a survival advantage residual acute myeloid leukemia cells, possibly contributing disease recurrence. mechanisms by which stroma in the regulates remain largely unknown. Using reverse-phase protein array technology, we profiled 53 key molecules 11 signaling pathways 20 primary samples and two cell lines, aiming understand stroma-mediated modulation response targeted agents temsirolimus (MTOR), ABT737 (BCL2/BCL-XL), Nutlin-3a (MDM2), identify effective combination therapy targeting context of microenvironment. Stroma reprogrammed networks modified sensitivity all three inhibitors. activated AKT at Ser473 majority treated with single-agent or Nutlin-3a. This mechanism was partially abrogated concomitant treatment plus Mapping revealed that combinations inhibitors increased number affected proteins multiple parallel signaling, translating into facilitated death. These results demonstrated mechanism-based selection combined can be used guide clinical drug tailor regimens eliminate microenvironment-mediated resistance leukemia.