Antagonism of the inhibitor of apoptosis protein (IAP) family was proposed as a novel method to induce apoptosis in cancer cells. However, it is become increasingly clear that the mechanism of action of IAP inhibitors is more complex than first assumed. The induction of apoptosis in cancer cells by IAP antagonists requires the presence of TNF-α, suggesting tumour cells much be inherently sensitive to TNF-α-mediated cell death. IAPs also regulate NF-κB activation, and as such can dictate the activity of cells of the immune system, thereby may influence the outcome of anti-cancer treatment in vivo.
We found that despite showing molecular sensitivity in vitro to the IAP antagonist LCL-161 (i.e. cIAP degradation and NF-κB activation), Eμ-myc B cell lymphoma cells were not sensitive to LCL-161-mediated cell death. Even more strikingly, we found LCL-161 significantly enhanced the growth of lymphoma in vivo,as treated mice had extensive tumour burden and succumbed to lymphoma significantly earlier than control-treated mice. Further investigation revealed Eμ-myc lymphoma cells were inherently refractory to death via the extrinsic apoptosis pathway and intriguingly that LCL-161 was not influencing the proliferation of lymphoma cells either in vitro or in vivo. In fact, LCL-161 treatment appeared to be deregulating anti-tumour immunity, and LCL-161 treated mice were significantly more sensitive to LPS-mediated septic shock. As septic shock is the primary lethal complication of patients with haematological malignancies, we recommend that the effects of IAP antagonism on immune cells during cancer treatment should be thoroughly examined prior to further clinical trials.