Signaling: the summary

The evidence that I have summarized over the past couple of weeks taken from the B J Haem paper suggests that PTKs and their downstream pathways are constitutively active in CLL. Selective inhibitors of some of these pathways induce apoptosis of CLL cells by mechanisms that converge through downregulation of anti-apoptotic MCL-1 and other anti-apoptotic proteins. Expression of MCL-1 by CLL cells correlates with poor prognosis, suggesting a key role for this protein in maintaining apoptosis resistance.

However, detailed mechanisms linking PTKs or their downstream pathways to regulation of these anti-apoptotic proteins have not been established. In particular, the precise roles of the Mek/Erk, PI-3k/Akt and mTor pathways in maintaining apoptosis resistance of CLL cells require further study.

Several studies have resulted in identification of novel agents that may lead to improved therapy, overcoming some of the deficiencies of conventional drugs. For example, Ror1 antisera, the CDK inhibitor SNS-032 and the NF-κB inhibitor LC1 kill CLL cells irrespective of prognostic factors. Other potential drugs including inhibitors of Syk, 2009, Abl, Ck2 and Pkc δ appear to be more effective against isolates from patients with aggressive compared to stable CLL. Loss of genes encoding TP53 or its upstream activator ATM identify a particularly poor prognosis subset of patients, due to the dependence of conventional cytotoxic agents on the TP53 pathway. It is therefore relevant that the NF-κB inhibitor parthenolide, roscovitine, flavopiridol and the Hsp70 inhibitor PAS have potential worthy of further investigation because they all act independent of TP53/ATM status.

An additional potential advantage of signal-transduction-based therapeutics is that many of the agents described here kill CLL cells at concentrations which have low toxicity towards normal T or B cells. Furthermore, Hsp90 inhibitors, the NF-κB inhibitor parthenolide and the Hsp70 inhibitor PAS are minimally toxic to haematopoietic stem cells. Finally, killing by several signal transduction inhibitors is unlike that by conventional drugs, because it is unaffected by protective signals from stromal cells.

The selection of drugs that will be most effective clinically in CLL treatment remains a formidable problem. On theoretical grounds, it may be expected that agents like Hsp70 and Hsp90 inhibitors, which destabilize key proteins operating at different levels of anti-apoptotic signaling cascades, may ultimately prove most effective. This is provided that barriers to their use may be solved by generation of novel inhibitors with improved pharmacokinetic and pharmacodynamic properties and resolution of the issue of scheduling. An alternative approach would involve the combination of two or more inhibitors that induce apoptosis by targeting different proteins. Combinations of two or more of these novel agents may result in greater selectivity against CLL cells by decreasing the concentrations of each pro-apoptotic agent required. Effective combinations may be identified through rigorous ex vivo evaluation of synergy by established procedures and is the next logical step in extending the therapeutic use of signaling inhibitors in CLL treatment.