| Acute myelogenous leukemia (AML) five year survival ranges between 20-30% despite the administration of the most intensive chemotherapy regimen, hence the need to develop new therapeutic strategies. Substantial inter-patient variation in sensitivity to AVE9633, a very promising anti-CD33 immunoconjugate, was observed. The goal of this project is to identify the mechanisms underlying resistance of AML cells to AVE9633. Using the AVE9633 sensitive AML cell line, HL60, and its resistant variant HL60/s, we found that both internalize the immunotoxin to a similar extent. The uncoupling of the antibody from the CD33 receptor is significantly lower in HL60/s. CD33 degradation was seen to be reduced in the resistant cell line while Suppressor Of Cytokine Signalling 3, SOCS3, playing a role in CD33 degradation, is only expressed in the sensitive cell line. In conclusion, antibody-receptor uncoupling and CD33 degradation defects were shown to be associated with resistance to AVE9633 in the HL60/s cell line. The identification of these mechanisms of resistance could provide means to screen-out patients most likely to benefit from treatment with AVE9633 and identify new approaches to treat patients refractory to current cancer treatments. |
