A combinatorial drug screen in PDX-derived primary rhabdomyosarcoma cells identifies the NOXA - BCL-XL/MCL-1 balance as target for re-sensitization to first-line therapy in recurrent tumors

Neoplasia. 2021 Sep;23(9):929-938. doi: 10.1016/j.neo.2021.07.001. Epub 2021 Jul 27.

Abstract

First-line therapy for most pediatric sarcoma is based on chemotherapy in combination with radiotherapy and surgery. A significant number of patients experience drug resistance and development of relapsed tumors. Drugs that have the potential to re-sensitize relapsed tumor cells toward chemotherapy treatment are therefore of great clinical interest. Here, we used a drug profiling platform with PDX-derived primary rhabdomyosarcoma cells to screen a large drug library for compounds re-sensitizing relapse tumor cells toward standard chemotherapeutics used in rhabdomyosarcoma therapy. We identified ABT-263 (navitoclax) as most potent compound enhancing general chemosensitivity and used different pharmacologic and genetic approaches in vitro and in vivo to detect the NOXA-BCL-XL/MCL-1 balance to be involved in modulating drug response. Our data therefore suggests that players of the intrinsic mitochondrial apoptotic cascade are major targets for stimulation of response toward first-line therapies in rhabdomyosarcoma.

Keywords: BCL-2 family proteins; PDX-derived primary cells; Re-sensitization; Recurrent tumors; Rhabdomyosarcoma.

Publication types

  • Research Support, Non-U.S. Gov't