Model of UCN-01 and MEK1/2 inhibitor interactions in MM cells.

The DNA damage response genes ATM andATR activate Chk1, which phosphorylates the Cdc25C phosphatase, leading to its proteasomal degradation. Inhibition of Chk1 phosphorylation results in activation of p34^cdc2, which, if unscheduled, leads to apoptosis. UCN-01, by inhibiting Chk1 phosphorylation, spares Cdc25C, which in turn promotes activation (dephosphorylation) of p34^cdc2. The putative proapoptotic actions of activated p34^cdc2 may be opposed by a compensatory activation of the cytoprotective Raf/MEK/MAP kinase cascade, which is also stimulated by several MM survival factors, including IL-6, IGF-1, and integrins. Blocking the MEK/MAP kinase cascade (eg, by pharmacologic MEK1/2 inhibitors) downstream of IL-6–, IGF-1–, and integrin-related actions (eg, fibronectin, FN) may thus render MM cells particularly vulnerable to the lethal actions of UCN-01. The contribution of the NFκB axis, which is linked to both ERK1/2 and PI3K/Akt (dashed lines), to these events remains to be fully elucidated. Finally, the possibility that MEK1/2 inhibitors act directly on cdc2 regulatory molecules (ie, cdc25C, or Wee1) cannot be excluded.