The novel anti-MEK small molecule AZD6244 induces BIM-dependent and AKT-independent apoptosis in diffuse large B-cell lymphoma

Abstract

IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common lymphoid malignancy in adults accounting for nearly 35% of all non-Hodgkin lymphomas (NHL). Significant advances have been in the treatment of DLBCL, particularly with immunochemotherapy, however approximately 30%-40% of patients still die from this malignancy. In addition, short-and long-term toxicities of chemotherapy, including secondary malignancies and leukemias, continue to adversely impact the long-term prognosis of patients. Continued investigations of novel targeted therapeutic agents in DLBCL are warranted.The RAS/RAF/mitogen-activated protein kinase 1/2 (MEK1/2)/ extracellular signal-regulated kinase 1/2 (ERK1/2) plays a prominent role in cancer biology, including hematologic malignancies, in part through the regulation of cell growth and proliferation. [1][2][3][4][5] Activating mutations in RAS and RAF lead to aberrant activation of their downstream target, MEK1/2. Directly downstream of MEK1/2, ERK1 and ERK2 are intimately involved in transducing signals from growth factor receptors and cytokine receptors after ligand binding. 2 Furthermore, ERK is the only known catalytic substrate of MEK. 6 We and others have shown that the MEK/ERK signaling pathway is constitutively active in a large number of cancers, including hematologic malignancies. 3,4,[7][8][9] Moreover, the MEK/ERK signal transduction cascade has been shown to be susceptible to pharmacologic intervention. Thus, MEK has emerged as an attractive therapeutic target in cancer.The majority of preclinical, and especially clinical trial data studying MEK inhibitors to date have emerged largely from solid tumor studies. [10][11][12][13][14] We recently showed in preclinical studies that inhibition of ERK1/2 phosphorylation by 1st generation MEK and ERK inhibitors correlated with significant cell death in a lymphoma tumor model, 15 while others showed that sublethal concentrations of a 1st generation MEK antagonist potentiated the effect of sorafemib in lymphoma cells. 16 Furthermore, we recently demonstrated that MCT-1, an oncogene directly downstream of MEK/ ERK, is over-expressed in the majority of primary DLBCLs. 15 MCT-1 is known to colocalize with ERK1/2, while phosphorylation of MCT-1 protein by ERK is critical for stabilization of MCT-1 protein and for its functional ability to promote cell proliferation. 15,17 ARRY-142886 (AZD6244, selumetinib; Astra Zeneca) is a selective nonATP-competitive 2nd generation oral MEK inhibitor studied primarily in solid tumor studies with reported nanomolar activity against purified MEK1 enzyme. [18][19][20][21][22][23] Furthermore, phase 1 and phase 2 solid tumor clinical trials have shown this agent to be well-tolerated and have encouraging clinical efficacy. [24][25][26][27] To our knowledge, minimal data are available on newer generation MEK inhibitors in lymphoma and moreover, this anti-MEK agent has never been examined in lymphoma. We sought to examine the mechanisms of action and cytotoxic effect of the novel 2nd generation MEK sma...

Suppression of Ras/Mapk pathway signaling inhibits Myc-induced lymphomagenesis

“…Recently, a pharmacological MEK inhibitor was shown to kill human diffuse large B-cell lymphoma cells, which frequently overexpress Myc. 40 Thus, a likely fruitful avenue of investigation will be to determine whether Ras/Mapk pathway signaling is critical for the maintenance and survival of lymphomas and the many other cancers that overexpress Myc.…”

MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner

“…Because the RAS/MEK/ ERK pathway is known to be important for cancer cell signaling and survival, MEK targeting may inhibit the growth of some malignant cells resistant to transplant conditioning in the critical early interval after transplantation. Indeed, recent studies of acute myeloid leukemia, 37 multiple myeloma, 38 cutaneous T-cell lymphomas 39 and diffuse large B-cell lymphoma 40 have demonstrated that MEK inhibition may have significant therapeutic value as antineoplastic agents in the setting of hematologic malignancies known to be responsive to allogeneic SCT.…”

Mutant BRAF upregulates MCL-1 to confer apoptosis resistance that is reversed by MCL-1 antagonism and cobimetinib in colorectal cancer.

“…MCL-1 is known to bind to and neutralize BIM and BAK (49), and release of BIM from MCL-1 contributes to apoptosis induction. Studies have shown that BIM induction is an important mechanism by which MEK/ERK inhibitors, including cobimetinib, can cooperatively kill tumor cells (50)(51)(52). Whereas ERK phosphorylation of BIM targets the protein for polyubiquitination and proteosomal degradation (53), we previously reported that the MEK/ERK inhibitor, GDC-0623, inhibits BIM phosphorylation at Ser 69 to increase protein stability (50).…”