Sequential combinations of chemotherapeutic agents with BH3 mimetics to treat rhabdomyosarcoma and avoid resistance

Clara Alcon, Albert Manzano-Muñoz, Estela Prada, Jaume Mora, Aroa Soriano, Gabriela Guillén, Soledad Gallego, Josep Roma, Josep Samitier, Alberto Villanueva, Joan Montero

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number634
Pages (from-to)634
Number of pages13
JournalCell Death & Disease
Volume11
Issue number8
DOIs
Publication statusPublished - 1 Aug 2020

Keywords

  • APOPTOSIS
  • BAK
  • BCL-2
  • BCL-X(L)
  • BIOLOGY
  • CELLS
  • INDUCTION
  • INHIBITION
  • MCL-1
  • TISSUE

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