Dual inhibition of BCL-2 and Aurora A synergizes to induce apoptosis in MYCN-amplified neuroblastoma.
Major finding: Dual inhibition of BCL-2 and Aurora A synergizes to induce apoptosis in MYCN-amplified neuroblastoma.
Mechanism: Sensitivity to ABT-199 is mediated by MYCN-induced expression of the proapoptotic NOXA protein.
Impact: Dual treatment with ABT-199 and MLN8237 may be effective in patients with MYCN-amplified neuroblastoma.
Many high-risk neuroblastomas have MYCN amplification, which is associated with a poorer outcome. However, it has proven difficult to directly target MYCN, indicating that additional therapies are needed. In order to identify potential therapies, Ham, Costa, and colleagues analyzed data from a high-throughput drug-sensitivity screen of solid tumors. Neuroblastoma cell lines with MYCN amplification were highly sensitive to ABT-263 (navitoclax), an inhibitor of the prosurvival BCL-2 and BCL-xL proteins. Analysis of MYCN-amplified and MYCN wild-type primary neuroblastomas revealed that MYCN amplification is associated with increased expression of the proapoptotic MCL-1 inhibitor NOXA, which is encoded by PMAIP1. Knockdown of NOXA protected MYCN-amplified cells from ABT-263–induced apoptosis, and MYCN knockdown reduced expression of NOXA, indicating that upregulation of NOXA by MYCN sensitized cells to ABT-263. Chromatin immunoprecipitation experiments demonstrated that MYCN binds to the PMAIP1 promoter, suggesting that it upregulates NOXA directly. MYCN-amplified neuroblastomas had higher expression of BCL-2 compared to BCL-xL, and showed similar sensitivity to ABT-199 (venetoclax), a BCL-2-specific inhibitor with decreased toxicity, making it attractive for combination therapy. A combination drug screen identified an Aurora A inhibitor, MLN8237 (alisertib), as a potent inducer of apoptosis that synergized with ABT-199. Combination treatment with MLN8237 and ABT-199 synergistically induced apoptosis in MYCN-amplified, but not wild-type, neuroblastoma cells. MLN8237 reduced expression of MCL-1 and disrupted BIM–MCL-1 complexes, and siRNA-mediated knockdown of MCL-1 had a similar effect as MLN8237 in inducing apoptosis in ABT-199–treated cells. The ABT-199/MLN8237 combination was also effective in vivo in MYCN-amplified cell line–derived and patient-derived xenografts, resulting in tumor regression and sustained remission without toxicity. Altogether, these results indicate that combined inhibition of BCL-2 and Aurora A effectively induces apoptosis and tumor regression in MYCN-amplified neuroblastoma in part by reducing NOXA expression, and suggest that this combination should be further studied in clinical trials of high-risk MYCN-amplified neuroblastoma.
Ham J, Costa C, Sano R, Lochmann TL, Sennott EM, Patel NU, et al. Exploitation of the apoptosis-primed state of MYCN-amplified neuroblastoma to develop a potent and specific targeted therapy combination. Cancer Cell 2016;29:159–72.
- ©2016 American Association for Cancer Research.