Signal interception-based therapies--a double-edged sword in Bcr/abl-induced malignancies?

Imatinib was a major breakthrough in the treatment of Bcr/abl-positive leukemias. The effectiveness and value of this drug is limited by the emergence of resistance. Alternative drug targets may be identified by analyzing the downstream signaling network including the Jak/Stat-pathway, Ras-dependent signaling, PI3-kinases (PI3K), or the nuclear transcription factors onto which these pathways impinge. However, several factors limit the possible suitability of a drug target: (i) tissue-specific versus ubiquitous expression of the target; (ii) redundancy within the signaling network; and (iii) off-target effects on the immune system. Although the former two aspects are well appreciated as limiting factors, the latter has not been addressed so far. The advent of genetically engineered mice provides a sophisticated target validation in vivo as well as analysis of interactions between the immune system and tumor cells. Based on studies in such mouse models, we predict that many targeted compounds including PI3Kdelta-inhibitors, could act as double-edged swords because their beneficial action on tumor cells may be neutralized or even overwhelmed by their additional immunosuppressive effects.