Preclinical evaluation of drug combinations identifies co-inhibition of Bcl-2/XL/W and MDM2 as a potential therapy in uveal melanoma

Didier Decaudin; Estelle Frisch Dit Leitz; Fariba Nemati; Malcy Tarin; Adnan Naguez; Mohamed Zerara; Benjamin Marande; Raquel Vivet-Noguer; Ensar Halilovic; Claire Fabre; Aart Jochemsen; Sergio Roman-Roman; Samar Alsafadi

doi:10.1016/j.ejca.2019.12.012

Preclinical evaluation of drug combinations identifies co-inhibition of Bcl-2/XL/W and MDM2 as a potential therapy in uveal melanoma

Eur J Cancer. 2020 Feb:126:93-103. doi: 10.1016/j.ejca.2019.12.012. Epub 2020 Jan 9.

Affiliations

¹ Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University, Paris, France; Department of Medical Oncology, Institut Curie, Paris, France.
² Uveal Melanoma Translational Group, Department of Translational Research, Institut Curie, PSL Research University, Paris, France.
³ Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University, Paris, France.
⁴ Novartis Institutes for Biomedical Research, Cambridge, MA, USA.
⁵ Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands.
⁶ Uveal Melanoma Translational Group, Department of Translational Research, Institut Curie, PSL Research University, Paris, France. Electronic address: [email protected].

PMID: 31927215
DOI: 10.1016/j.ejca.2019.12.012

Abstract

Introduction: Uveal melanoma (UM) is a rare and malignant intraocular tumour with a dismal prognosis. Despite a good control of the primary tumour by radiation or surgery, up to 50% of patients subsequently develop metastasis for which no efficient treatment is yet available.

Methodology: To identify therapeutic opportunities, we performed an in vitro screen of 30 combinations of different inhibitors of pathways that are dysregulated in UM. Effects of drug combinations on viability, cell cycle and apoptosis were assessed in eight UM cell lines. The best synergistic combinations were further evaluated in six UM patient-derived xenografts (PDXs).

Results: We demonstrated that the Bcl-2/X_L/W inhibitor (ABT263) sensitised the UM cell lines to other inhibitors, mainly to mammalian target of rapamycin (mTOR), mitogen-activated protein kinase kinase (MEK) and murine double minute 2 (MDM2) inhibitors. mTOR (RAD001) and MEK1/2 (trametinib) inhibitors were efficient as single agents, but their combinations with ABT263 displayed no synergism in UM PDXs. In contrast, the combination of ABT263 with MDM2 inhibitor (HDM201) showed a trend for a synergistic effect.

Conclusion: We showed that inhibition of Bcl-2/X_L/W sensitised the UM cell lines to other treatments encouraging investigation of the underlying mechanisms. Furthermore, our findings highlighted Bcl-2/X_L/W and MDM2 co-inhibition as a promising strategy in UM.

Keywords: Bcl-2/XL/W; Drug screening; Drug synergism; MDM2; Patient-derived xenografts; Uveal melanoma.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aniline Compounds / administration & dosage
Animals
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Apoptosis Regulatory Proteins / antagonists & inhibitors
Apoptosis Regulatory Proteins / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Drug Combinations
Drug Evaluation, Preclinical / methods*
Everolimus / administration & dosage
Humans
Imidazoles / administration & dosage
Melanoma / drug therapy*
Melanoma / metabolism
Melanoma / pathology
Mice
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases / metabolism
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 / metabolism
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2 / metabolism
Pyridones / administration & dosage
Pyrimidines / administration & dosage
Pyrimidinones / administration & dosage
Pyrroles / administration & dosage
Sulfonamides / administration & dosage
TOR Serine-Threonine Kinases / antagonists & inhibitors
TOR Serine-Threonine Kinases / metabolism
Uveal Neoplasms / drug therapy*
Uveal Neoplasms / metabolism
Uveal Neoplasms / pathology
Xenograft Model Antitumor Assays / methods
bcl-X Protein / antagonists & inhibitors
bcl-X Protein / metabolism

Substances

Aniline Compounds
Apoptosis Regulatory Proteins
BCL2L2 protein, human
Drug Combinations
Imidazoles
Proto-Oncogene Proteins c-bcl-2
Pyridones
Pyrimidines
Pyrimidinones
Pyrroles
Sulfonamides
bcl-X Protein
siremadlin
trametinib
Everolimus
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
MTOR protein, human
TOR Serine-Threonine Kinases
Mitogen-Activated Protein Kinase Kinases
navitoclax