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We show that immunoprecipitation - Tandem mass spectrometry in H929 multiple myeloma cancer cells resulted in the discovery of a rare and unexpected BCR-ABL fusion, which led to the formation of a therapeutic intervention using imatinib. BCR-ABL fusion in H929 cells was confirmed by three independent IP-MS experiments central to cell signaling pathways: phosphotyrosine peptide IP, p85 regulatory subunit of phosphoinositide-3-kinase IP, and the GRB2 adaptor IP. The tyrosine kinase enzyme kinase activity, as well as p85 IP, informs the enzyme kinases and receptor tyrosine kinases involved in AKT activation, while GRB2 IP identifies RTKs and adaptors leading to ERK activation. These results reveal a framework for directed proteomics from patient tumor samples for selecting the appropriate TKI inhibitor based on IP and LC-MS/MS. According to the data, MM patients, not CML patients, might benefit from BCR-ABL diagnostic testing.
However, almost all patients recover after acquiring drug resistance, with resistance-causing genetic abnormalities limited to just a small subset of cases. In vitro and in vivo, overexpression of CDK6 in several myeloma cell lines reduces sensitivity to IMiDs, while CDK6 inhibition by proteolysis targeting chimeras is highly synergistic with IMiDs, with chimeras. CDK6 upregulation is a druggable target in IMiD-resistant multiple myeloma, according to this research, and proteomic studies can help identify non-genetic resistance mechanisms in cancer.
In MM patients with osteolytic disease, bone marrow plasma activin A levels were elevated. MM cell-engagement of marrow stromal cells has resulted in enhanced activation of A secretion by adhesion-mediated JNK activation. In an in vivo humanized MM model, targeting activin A by a soluble decoy receptor slowed osteoblast inhibition, improved MM bone disease, and cut tumor formation, setting the stage for human clinical trials.
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