Toxin-Based Therapeutic Approaches

Shapira, Assaf; Benhar, Itai

In contrast to the enzymatically active polypeptide of PE, DT and RIPs, which strongly inhibit protein synthesis causing the death of the intoxicated cell (see above), inactivation of mitogenactivated protein kinase kinases by the action of anthrax lethal factor (LF) was found to selectively kill cells in which an activated MAPK pathway is required for their survival. This is similar to observed for cells bearing the V600E mutation in B-Raf, a serine/threonine kinase immediately upstream of MEK1/2 in the of the ERK MAPK cascade. The mutation, which was demonstrated mainly in melanoma but also in other human malignancies, "locks" the molecule in a constitutively active state, making the cell dependent on the constitutive activation of the ERK pathway for survival [480] [481] [482] [483] . However, although specific toxicity toward B-Raf mutant melanoma cells has been observed both in vitro and in xenograft melanoma tumors in mice [481] [482] [483] [484] , development of LeTx variants with lower in vivo toxicity and high tumor specificity would be required for use in human cancer patients [485] .