Amplification and overexpression of the myeloid cell leukemia differentiation protein MCL1 and the murine double minute protein MDM2 have been reported in various human tumors as well as hematological malignancies including acute myeloid leukemia (AML).
Using reverse-phase protein array technology, we profiled 53 key protein molecules in 11 signaling pathways in 20 primary acute myeloid leukemia samples and two cell lines, aiming to understand stroma-mediated signaling modulation in response to the targeted agents temsirolimus (MTOR), ABT737 (BCL2/BCL-XL), and Nutlin-3a (MDM2), and to identify the effective combination therapy targeting acute myeloid leukemia in the context of the leukemia microenvironment.
Predictive biomarkers for response to MDM2 inhibitors have been proposed, but they require further validation both in vitro and in vivo so that the accumulated knowledge concerning pathological p53 dysregulation in leukemia and novel molecular-targeted strategies to overcome this dysregulation can be translated safely and efficiently into novel clinical therapeutics.
Two clinical-stage anticancer drugs, the Bcl-2 inhibitor ABT-263, and the MDM2 inhibitor SAR405838 achieve complete tumor regression in animal models of leukemia but also induce acquired resistance.
In conclusion, the results of our meta-analysis suggest that the MDM2T309G polymorphism can increase the risk of leukemia, especially among Asian populations.
These findings highlight MDM2 as a potential therapeutic target to increase TKI-mediated apoptosis and imply that the combination of PI3K/mTOR inhibitor and TKI might form a novel strategy to combat TKI-resistant BCR-ABL1 positive leukemia.
The overall data indicated a significant association of the MDM2T309G polymorphism with leukemia risk (GG vs. TT: odds ratio [OR] = 1.62; 95% confidence interval [CI] = 1.14-2.29; dominant model: OR = 1.20; 95% CI = 1.06-1.36; recessive model: OR = 1.47; 95% CI = 1.07-2.03).
Using data from ex vivo MDM2 inhibitor treatment of a large cohort of molecularly highly characterized CLL cases, we were able to demonstrate the central role of p53 status as a determinant of resistance in this common leukemia.