Copy number gain of the MCL1 gene locus (1q21) and acquisition of BCL2 mutation mediate resistance to venetoclax in multiple myeloma (MM) patients

Mechanisms of venetoclax resistance and solutions

“…identified a copy number amplification of the MCL-1 gene locus (1q21) in MM-resistant cells. Upon relapse, cells with this mutation became the dominant clone of MCL-1 high-expressing cells, suggesting that the elevated MCL-1 expression caused by the increased copy number of the 1q21 locus leads to venetoclax resistance ( 40 ).…”

“…The results of immunoprecipitation show that, both mutations weaken the ability of venetoclax to bind to BCL-2 and make the cells resistant ( 76 ). In MM cells, another resistance mutation Aps111Ala largely eliminates the venetoclax-induced dissociation of BIM from BCL-2, reducing the sensitivity of the MM-sensitive cell line KMS12PE to venetoclax by approximately 7.5-fold ( 40 ). In addition to the mutation described above, Ghia et al.…”

“…In addition to detecting the cellular immunophenotype, the copy number variation in the 1q21 region of the MCL-1 gene also predicts the sensitivity of cells to venetoclax. If amplification of the 1q21 region in MM cells is detected during treatment, it often suggests elevated MCL-1 expression and the development of resistance ( 40 ). In metabolic studies, the level of fatty acid metabolism was reported to correlate significantly with the patient response to combination therapy of venetoclax and azacitidine, and increased fatty acid metabolism during treatment suggested drug resistance ( 57 ).…”