Molecular oncology. Causes of cancer and targets for treatment. Cambridge University Press (2014)
Cancer therapy targeting extrinsic apoptosis is usually focused on promoting death-receptor expression and oligomerization, decreasing decoy-receptor expression, and decreasing cFLIP levels (159–160). Notably, TRAIL and TRAIL-receptor agonists provide significant potential for cancer therapy because of their specificity to kill tumor cells over normal cells, possibly due to over-expression of TRAIL decoy receptors by normal cells (159). Modulating extrinsic apoptosis in cancer cells can restore cancer cell sensitivity to TRAIL (161). However, there are still many tumor types (~50%) that are resistant to TRAIL-induced apoptosis (162). Delineation of the detailed molecular pathways through basic research will be a key to the development of new effective therapeutics. For example, it has been shown that leukemogenic tyrosine kinases Bcr-Abl, FLT3/D835Y, and Tel-PDGFRβ can all suppress Apaf-1 apoptosome activation and cell death by indirectly suppressing phosphorylation of Hsp90 . Through this mechanism, leukemogenic tyrosine kinases facilitate Hsp90 inhibition of Apaf-1, conferring imatinib (Gleevac) resistance and inspiring the development of cleaver strategies for targeted therapies (163).