BMI1-Inhibitor PTC596 in Combination with MCL1 Inhibitor S63845 or MEK Inhibitor Trametinib in the Treatment of Acute Leukemia.

PURPOSE

Prognosis for acute myeloid leukemia (AML) patients is poor, particularly in mutated AML, secondary, relapsed, and refractory AML, and in patients unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds targeting the stem cell oncoprotein BMI1 and activating the tumor suppressor protein p53 may represent a promising novel treatment option for poor risk AML patients.

EXPERIMENTAL DESIGN

The BMI1 inhibitor PTC596, MCL1 inhibitor S63845, and MEK inhibitor trametinib, as well as the p53 activator APR-246 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including and wild type, mutant and wild type, as well as mutant and wild type AML cell lines and a variety of patient derived AML cells.

RESULTS

AML cell lines were variably susceptible to PTC596 and to combination treatments with PTC596 and MCL1 inhibitor S63845, MEK inhibitor trametinib, or activator APR-246, independent of mutational status. Susceptibility of patient samples for PTC596 in combination with S63845 or trametinib was significant for the majority of adverse risk primary and secondary AML with minimal efficacy in favorable risk AML, and correlated significantly with CD34 positivity of the samples. and gene expression, and MCL1 and MEK1 protein levels were identified as biomarkers for response to PTC596 combination treatments.

CONCLUSIONS

The combination of PTC596 and S63845 may be an effective treatment in CD34+ adverse risk AML with elevated gene expression and MCL1 protein levels, while PTC596 and trametinib may be more effective in CD34+ adverse risk AML with elevated gene expression and MEK protein levels.