Elucidation of Acquired Resistance to Bcl-2 and MDM2 Inhibitors in Acute Leukemia In Vitro and In Vivo

Abstract

Purpose 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. Elucidation of acquired resistance mechanisms and development of strategies to overcome the resistance are critical for their successful clinical development. Experimental Design We employed RS4;11 and MV4;11 cell lines, two acute leukemia models, to investigate acquired resistance mechanisms for both drugs in vitro and in vivo and evaluated several treatment regimens in xenograft mouse models to improve long-term, complete tumor regression. Results Resistance to either SAR405838 or ABT-263 (or its analogue ABT-737) develops in acute leukemia models in vitro and in vivo. RS4;11 and MV4;11 tumors treated with SAR405838 acquire resistance to the drug by mutation of the p53 gene or compromise of p53 function. RS4;11 tumors treated with either ABT-263 or ABT-737 acquire resistance primarily through down-regulation of BAX but not BAK. When acute leukemia cells become highly resistant to the MDM2 inhibitor, they retain their sensitivity to the Bcl-2 inhibitors, or vice versa. Certain sequential or combination treatment of SAR405838 and ABT-263 can achieve longer-term tumor regression than treatment with either agent alone. Conclusion Our study provides new insights into the mechanisms of acquired resistance of Bcl-2 and MDM2 inhibitors in acute leukemia models and suggests that certain sequential or combination treatment of these two distinct classes of apoptosis-inducing agents should be tested as new treatment strategies for acute leukemia in the clinic.

Resistance mechanisms to TP53-MDM2 inhibition identified by in vivo piggyBac transposon mutagenesis screen in an Arf −/− mouse model

“…4A). This is in line with previously reported data identifying TP53 mutagenesis as a major mechanism of resistance to TP53-MDM2 inhibitors, for either intrinsic resistance (7) or induced resistance (40)(41)(42). Trp53 exons sequencing of all our resistant DNA samples also identified Trp53 somatic mutations in 13 out of 95 resistant tumors (Fig.…”

“…S8B). Collectively, these data suggest that a fraction of patients with TP53 wild-type tumors might benefit from a dual treatment with BCL-2/BCL-xL inhibitor and MDM2 inhibitor, consistent with previous observations in leukemia that combination treatment of MDM2 inhibitor and ABT-263 could achieve longer-term tumor regression (41).…”

Mcl-1 downregulation leads to the heightened sensitivity exhibited by BCR-ABL positive ALL to induction of energy and ER-stress

“…In addition to the AMPK/mTOR pathway, we uncovered that the UPR/PERK/p-eIF2α pathway also contributes to the translational downregulation of Mcl-1 expression in BCR-ABL+ ALL cells undergoing ER-stress. Interestingly, ER-stress-induced phosphorylation of eIF2α was recently found to be coupled with mitochondrial control of apoptosis via translational repression of Mcl-1 [42]. Based on the new function we recently reported for AMPK in sensing ER-stress in addition to sensing energy stress [17, 19], these findings suggest that Mcl-1 expression is translationally downregulated by energy stress via AMPK/mTOR pathway, and by ER-stress via both the UPR/PERK/eIF2α and AMPK/mTOR pathways.…”

Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer

“…Conventional cell viability, Annexin V-propidium iodide apoptosis, cell cycle and immunoblotting analyses were performed as described previously (18,19). …”

“…Lentiviral vectors for human MCL1 shRNA was described previously (19). ON-TARGETplus CRBN and siCONTROL siRNAs were from Dharmacon.…”