PXD101 is a novel hydroxamate that potently inhibits the enzymatic activity of histone deacetylase (HDAC) at nanomolar concentration. In the present investigation, the growth-inhibitory activity of PXD101 monotherapy and combination therapy on human non-small cell lung cancer (NSCLC) samples was examined. When used as monotherapy, PXD101 inhibited the growth of a variety of NSCLC cell lines at sub to low micromolar potency. The activity of PXD101 used in combination with the EGFR-inhibitor erlotinib (Tarceva), an agent approved for the treatment of recurrent NSCLC, demonstrated additive to synergistic growth-inhibitory activity. PXD101 treatment decreased EGFR expression, a finding which may provide a mechanistic rationale for the observed biological results. The activity of PXD101/erlotinib on NSCLC cell lines harboring wild-type or mutationally activated EGFR is now being explored. Based on these in vitro findings, the ability of PXD101 monotherapy and combination therapy with Tarceva to inhibit the growth of NSCLC xenografts is currently being evaluated. The activity of PXD101 used in combination with additional agents that are approved or under investigation for the treatment of NSCLC [e.g., pemetrexed, docetaxel, paclitaxel, and bortezomib] will also be presented.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]