towards improved death receptor targeted therapy for ... - TI Pharma

TRAIL and Hsp90 inhibition
A549 cells. In H460 cells, minimal TRAIL‐induced Akt phosphorylation is detectable despite
the observation that the PI3K/Akt inhibitor LY294002 to some extent increased TRAIL‐
induced apoptosis. In resistant A549 cells, LY294002 co‐treatment enhanced TRAIL‐
induced apoptosis by 4‐fold. Thus, Akt could be a mediator of the 17‐AAG effect in NSCLC
cells. Perifosine, an Akt inhibitor, was described to increase TRAIL‐R2 receptor expression
and decrease the cellular FLICE‐inhibitory protein (cFLIP) in human lung cancer cell lines,
enhancing caspase‐8 activation [32]. ERK has generally been linked to TRAIL‐induced
proliferation [33;34]. The inhibition of ERK by PD098059 did hardly sensitize these NSCLC
cells for TRAIL and thus is unlikely to contribute to 17‐AAG enhancement of apoptosis.
Clinical trials using small molecule inhibitors of Hsp90, like 17‐AAG, 17‐DMAG, VER‐52269,
CNF2024, and IPI‐504 are currently being conducted [35]. Based on our results and
previous studies, targeting Hsp90 in combination with induction of apoptosis by TRAIL
might be of therapeutic value in the treatment of NSCLC.
Acknowledgements
This research was performed within the framework of project T3‐112 and T3‐103 of the
Dutch Top Institute Pharma.
‐ 95 ‐