1. Integrated molecular and functional characterization of the intrinsic apoptotic machinery identifies therapeutic vulnerabilities in glioma
- Author
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Fernandez, Elizabeth G, Mai, Wilson X, Song, Kai, Bayley, Nicholas A, Kim, Jiyoon, Zhu, Henan, Pioso, Marissa, Young, Pauline, Andrasz, Cassidy L, Cadet, Dimitri, Liau, Linda M, Li, Gang, Yong, William H, Rodriguez, Fausto J, Dixon, Scott J, Souers, Andrew J, Li, Jingyi Jessica, Graeber, Thomas G, Cloughesy, Timothy F, and Nathanson, David A
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biological Sciences ,Genetics ,Precision Medicine ,Brain Disorders ,Cancer ,Rare Diseases ,Human Genome ,Cancer Genomics ,Brain Cancer ,Orphan Drug ,5.1 Pharmaceuticals ,Good Health and Well Being ,Cell Line ,Tumor ,Mitochondria ,Animals ,Humans ,Mice ,Glioma ,Brain Neoplasms ,Antineoplastic Agents ,Signal Transduction ,Apoptosis ,Gene Expression Regulation ,Neoplastic ,Tumor Suppressor Protein p53 ,Machine Learning - Abstract
Genomic profiling often fails to predict therapeutic outcomes in cancer. This failure is, in part, due to a myriad of genetic alterations and the plasticity of cancer signaling networks. Functional profiling, which ascertains signaling dynamics, is an alternative method to anticipate drug responses. It is unclear whether integrating genomic and functional features of solid tumours can provide unique insight into therapeutic vulnerabilities. We perform combined molecular and functional characterization, via BH3 profiling of the intrinsic apoptotic machinery, in glioma patient samples and derivative models. We identify that standard-of-care therapy rapidly rewires apoptotic signaling in a genotype-specific manner, revealing targetable apoptotic vulnerabilities in gliomas containing specific molecular features (e.g., TP53 WT). However, integration of BH3 profiling reveals high mitochondrial priming is also required to induce glioma apoptosis. Accordingly, a machine-learning approach identifies a composite molecular and functional signature that best predicts responses of diverse intracranial glioma models to standard-of-care therapies combined with ABBV-155, a clinical drug targeting intrinsic apoptosis. This work demonstrates how complementary functional and molecular data can robustly predict therapy-induced cell death.
- Published
- 2024