A NOXA/MCL-1 Imbalance Underlies Chemoresistance of Malignant Rhabdoid Tumor Cells

Malignant rhabdoid tumor (MRT) is a rare aggressive pediatric cancer characterized by inactivation of SNF5, a core subunit of SWI/SNF complexes. Previously, we showed that SNF5 contributes to transcriptional activation of NOXA, a pro-apoptotic protein that binds and inhibits the anti-apoptotic protein MCL-1. In this study, we found that NOXA expression was downregulated in MRT cell lines as well as in clinical MRT samples and that ectopically expressed NOXA bound MCL-1 and increased the sensitivity of MRT cell lines to doxorubicin (DOX) by promoting apoptosis. Consistent with this finding, knockdown of MCL-1 in MRT cell lines induced apoptosis and increased DOX sensitivity in MRT cells, and the MCL-1 inhibitor TW-37 synergized with DOX to induce MRT cell death. Our results suggest that modulation of the NOXA/MCL-1 pathway may be a potential strategy for the treatment of patients with MRT.