Function of the novel anti-MEK small molecule ARRY-142886 on large B-cell lymphoma.

Bhalla S, Evens AM, Dai B, Prachand S, Gordon LI, Gartenhaus RB. "Blood. 2011 Jul"

The RAS/RAF/MEK/ERK signaling pathway has become mostly unexplored like a possible therapeutic goal in lymphoma. The novel 2nd generation anti-MEK little molecule, ARRY-142886, down-regulated its direct downstream goal, phospho-ERK (pERK) in germinal center and nongerminal center diffuse significant B-cell lymphoma (DLBCL) cell lines and primary cells.

Similar diminished pERK levels had been famous regardless of constitutive activation (CA) of MEK. Consequently, numerous lymphoma-related ERK substrates were down-regulated by ARRY-142886 such as MCT-1, c-Myc, Bcl-2, Mcl-1, and CDK1/2. ARRY-142886 induced time- and dose-dependent antiproliferation and apoptosis in all DLBCL cell lines and fresh/primary cells (IC50 100nM-300nM). Moreover, ARRY-142886 resulted in drastically much less tumor compared with manage in an in vivo DLBCL SCID xenograft model.

Cell demise was related with cleaved PARP, caspases-8, -9, and -3, and apoptosis was caspase-dependent. In addition, there was stabilization of FoxO3a, activation of BIM and PUMA, plus a considerable decrease in c-Myc transcripts. In addition, siRNA knockdown of BIM abrogated selumetinib-related apoptosis inhibitor, although shRNA knockdown of ERK minimally sensitized cells. Lastly, manipulation of AKT with transfection of OCI-LY3 cells with CA-AKT or via chemical inhibition (LY294002) had minimum effect on ARRY-142886-induced cell loss of life.

Altogether, these findings show that the novel anti-MEK agent, ARRY-142886, induced apoptosis in DLBCL and that cell demise was BIM-dependent.