Among these, the anti-apoptotic protein Mcl-1, encoded by the Mcl-1 (myeloid leukemia cell-1) gene located on chromosome 1q21, has been implicated in the pathogenesis of various malignancies, particularly MM. As in numerous other malignancies, MM is characterized by dysregulation of apoptotic regulatory proteins of the Bcl-2 family. Multiple myeloma (MM) is a clonal accumulative disease of mature plasma cells which, despite recent treatment advances, is generally fatal. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Ĭompeting interests: The authors have declared that no competing interests exist. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was supported by awards CA100866, CA93738, and P50 CA142509-01 from the National Institutes of Health and the MMRF. Received: AugAccepted: JanuPublished: March 4, 2014Ĭopyright: © 2014 Pei et al. Gartel, University of Illinois at Chicago, United States of America (2014) Circumvention of Mcl-1-Dependent Drug Resistance by Simultaneous Chk1 and MEK1/2 Inhibition in Human Multiple Myeloma Cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM.Ĭitation: Pei X-Y, Dai Y, Felthousen J, Chen S, Takabatake Y, Zhou L, et al. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138 + MM cells, but not normal hematopoietic cells.

Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding.

Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease.

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