Circumvention of Mcl-1-Dependent Drug Resistance by Simultaneous Chk1 and MEK1/2 Inhibition in Human Multiple Myeloma Cells

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From: PLoS ONE(Vol. 9, Issue 3)
Publisher: Public Library of Science
Document Type: Article
Length: 9,369 words
Lexile Measure: 1550L

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Author(s): Xin-Yan Pei 1, Yun Dai 1, Jessica Felthousen 1, Shuang Chen 1, Yukie Takabatake 1, Liang Zhou 1, Leena E. Youssefian 1, Michael W. Sanderson 1, Wesley W. Bodie 1, Lora B. Kramer 1, Robert Z. Orlowski 2, Steven Grant 1,3,*

Introduction

Multiple myeloma (MM) is a clonal accumulative disease of mature plasma cells which, despite recent treatment advances, is generally fatal [1], [2]. As in numerous other malignancies, MM is characterized by dysregulation of apoptotic regulatory proteins of the Bcl-2 family [3], [4]. 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 [5], [6]. Mcl-1 promotes proliferation, tumorigenesis, and drug resistance of MM cells [3], [5]. Notably, whereas Mcl-1 represents a factor critical for MM cell survival [4], it has also been shown to confer resistance to the proteasome inhibitor bortezomib, one of the most active agents in current MM therapy [7]-[9]. Of note, Mcl-1 is over-expressed in cells from MM patients, and correlates with relapse and short survival [10]. Moreover, it is widely recognized that the bone marrow microenvironment (BMME) plays an important role in MM cell survival [2], [11], [12]. Furthermore, tumor-microenvironment interactions confer drug resistance to diverse drug classes [13], [14] and may limit the translational potential of promising pre-clinical approaches [11], [15]. Consequently, therapeutic strategies targeting tumor-microenvironment interactions represent an area of intense interest in MM [12], [16]. Significantly, several studies suggest that Mcl-1 also plays an important role in microenvironment-related form of drug resistance in MM [9], [17], [18].

Mcl-1 pro-survival activities have been primarily attributed to interactions with pro-apoptotic Bcl-2 family members such as Bak and Bim [19], [20], although this protein binds to multiple Bcl-2 family members. Mcl-1 expression is regulated at the transcriptional, translational, and post-translational levels [21], and is distinguished by a short half-life (e.g., 30 min to 3 h.) [5], [6]. This has prompted efforts to down-regulate Mcl-1 expression in MM and other Mcl-1-related malignancies e.g., utilizing CDK inhibitors/transcriptional repressors [20], [22] or translational inhibitors (e.g., sorafenib) [23], among others. An alternative strategy involves the use of BH3 mimetics which bind to and inactivate multi-domain anti-apoptotic proteins. While some of these (e.g. ABT-737 or ABT-199) display low avidity for and minimal activity against Mcl-1 [24], [25], others, including pan-BH3 mimetics such as obatoclax, act against this protein [19], [26]. However, the latter agent is no longer being developed clinically. Moreover, questions have arisen regarding the specificity of putative Mcl-1 antagonists [27]. Collectively, these considerations justify the search for alternative strategies capable of circumventing Mcl-1-related drug resistance.

Chk1 is a protein intimately involved in the DNA damage response [28], [29]. Exposure of MM cells to Chk1 inhibitors induces MEK1/2/ERK1/2 activation through a Ras- and Src-dependent mechanism. Moreover, interrupting this event by clinically relevant agents targeting the Src/Ras/MEK/ERK pathway synergistically induces MM cell apoptosis in vitro and in vivo [28], [30], [31]. Evidence that interruption of the MEK1/2/ERK1/2 pathway down-regulates Mcl-1 expression [32]...

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