Staff member publications
Alcon, Clara, Manzano-Muñoz, Albert, Montero, Joan, (2020). A new CDK9 inhibitor on the block to treat hematologic malignancies Clinical Cancer Research 26, (4), 761-763
CDK9-specific inhibition with AZD4573 impairs cancer-promoting gene expression such as MCL-1 and has been proven effective in hematologic malignancies preclinical models. This new clinical candidate should be further explored in the clinic not only as a monotherapy but also in combination with BH3 mimetics to prevent treatment resistance.
Alcon, Clara, Manzano-Muñoz, Albert, Prada, Estela, Mora, Jaume, Soriano, Aroa, Guillén, Gabriela, Gallego, Soledad, Roma, Josep, Samitier, Josep, Villanueva, Alberto, Montero, Joan, (2020). Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance Cell Death & Disease 11, (8), 634
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood and adolescence. Refractory/relapsed RMS patients present a bad prognosis that combined with the lack of specific biomarkers impairs the development of new therapies. Here, we utilize dynamic BH3 profiling (DBP), a functional predictive biomarker that measures net changes in mitochondrial apoptotic signaling, to identify anti-apoptotic adaptations upon treatment. We employ this information to guide the use of BH3 mimetics to specifically inhibit BCL-2 pro-survival proteins, defeat resistance and avoid relapse. Indeed, we found that BH3 mimetics that selectively target anti-apoptotic BCL-xL and MCL-1, synergistically enhance the effect of clinically used chemotherapeutic agents vincristine and doxorubicin in RMS cells. We validated this strategy in vivo using a RMS patient-derived xenograft model and observed a reduction in tumor growth with a tendency to stabilization with the sequential combination of vincristine and the MCL-1 inhibitor S63845. We identified the molecular mechanism by which RMS cells acquire resistance to vincristine: an enhanced binding of BID and BAK to MCL-1 after drug exposure, which is suppressed by subsequently adding S63845. Our findings validate the use of DBP as a functional assay to predict treatment effectiveness in RMS and provide a rationale for combining BH3 mimetics with chemotherapeutic agents to avoid tumor resistance, improve treatment efficiency, and decrease undesired secondary effects.