Model of the combination therapy using PPAR ligand and ERK cascade
inhibitors. The simultaneous inhibition of EGF
receptor-initiated ERK cascade activation by specific kinase inhibitors (-ibs)
or antibodies (-MABs) and supply of PPAR ligands (in tumors that have a need
for restored PPAR activity) will avoid: (a) ERK-mediated downregulation of PPAR through Ser84/114 phosphorylation,
(b) MEK1-driven nuclear export and cytoplasmic retention of PPAR, (c) activation of prosurvival and
proproliferative ERK cascade signaling by exogenous PPAR ligands (e.g., by TZD drugs) or
endogenous eicosanoid type of PPAR ligands (e.g., generated by
COX1/2), but is expected to (d) restore the differentiation-inducing and
proapoptotic functions of PPAR and its ligands, and (e) promote the transrepressive activity of PPAR on other promitotic and
proinflammatory transcription factors (e.g., AP1, ETS, STAT, NFκB). Legend: Yellow circles =
PPAR-ligand; TF = transcription factors; ROS = reactive oxygen species; GPCR
= G protein coupled receptor; RPTK = receptor protein tyrosine kinase; crm1 =
exportin1; NSAID = nonsteroidal anti-inflammatory drug; COX = cyclooxygenase;
-Ibs = LMW tyrosine kinase inhibitors; MABs = monoclonal tyrosine kinase
antibodies.
