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

Gabriele Manzella; Devmini C Moonamale; Michaela Römmele; Peter Bode; Marco Wachtel; Beat W Schäfer

doi:10.1016/j.neo.2021.07.001

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.

Authors

Gabriele Manzella¹, Devmini C Moonamale¹, Michaela Römmele¹, Peter Bode², Marco Wachtel¹, Beat W Schäfer³

Affiliations

¹ Department of Oncology and Children's Research Center, University Children's Hospital, Zurich, Switzerland.
² Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
³ Department of Oncology and Children's Research Center, University Children's Hospital, Zurich, Switzerland. Electronic address: [email protected].

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

MeSH terms

Aniline Compounds / therapeutic use
Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Cell Survival / drug effects
Cell Survival / genetics
Dose-Response Relationship, Drug
Doxorubicin / pharmacology
Doxorubicin / therapeutic use
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics
Drug Screening Assays, Antitumor / methods*
Etoposide / pharmacology
Etoposide / therapeutic use
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Myeloid Cell Leukemia Sequence 1 Protein / genetics*
Neoplasm Recurrence, Local / drug therapy
Neoplasm Recurrence, Local / genetics*
Neoplasm Recurrence, Local / pathology
Proto-Oncogene Proteins c-bcl-2 / genetics*
Rhabdomyosarcoma / drug therapy
Rhabdomyosarcoma / genetics*
Rhabdomyosarcoma / pathology
Sulfonamides / therapeutic use
Xenograft Model Antitumor Assays / methods
bcl-X Protein / genetics*

Substances

Aniline Compounds
Antineoplastic Agents
BCL2L1 protein, human
MCL1 protein, human
Myeloid Cell Leukemia Sequence 1 Protein
PMAIP1 protein, human
Proto-Oncogene Proteins c-bcl-2
Sulfonamides
bcl-X Protein
Etoposide
Doxorubicin
navitoclax