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Drug-Induced Death Signaling Strategy Rapidly Predicts Cancer Response to Chemotherapy
Open accessAbstract
There is a lack of effective predictive biomarkers to precisely assign optimal therapy to cancer patients. While most efforts are directed at inferring drug response phenotype based on genotype, there is very focused and useful phenotypic information to be gained from directly perturbing the patient's living cancer cell with the drug(s) in question. To satisfy this unmet need, we developed the Dynamic BH3 Profiling technique to measure early changes in net pro-apoptotic signaling at the mitochondrion ("priming") induced by chemotherapeutic agents in cancer cells, not requiring prolonged ex vivo culture. We find in cell line and clinical experiments that early drug-induced death signaling measured by Dynamic BH3 Profiling predicts chemotherapy response across many cancer types and many agents, including combinations of chemotherapies. We propose that Dynamic BH3 Profiling can be used as a broadly applicable predictive biomarker to predict cytotoxic response of cancers to chemotherapeutics in vivo.
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“BCL2-homology domain (BH3) profiling 41 demonstrated that cytochrome c release following mitochondrial exposure to pro-apoptotic BH3-only peptides (e.g. BIM BH3, PUMA BH3) was similar in control and Tbk1-null B16 cells (Extended Data Fig. 9a).”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [41]
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“Dynamic BH3 profiling robustly predicted which patients would respond to a given therapy across multiple cancer types.”
From Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate (2016) · cites this paper as [29]
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“Montero et al. recently reported a functional approach called ‘dynamic BH3 profiling’, in which therapeutics are applied to cell lines or clinical tumor isolates, and then the percentage of cells that undergo mitochondrial outer membrane permeabilization (MOMP) is measured after introduction of a pro-apoptotic BH3 peptide29.”
From Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate (2016) · cites this paper as [29]
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Metadata
- Authors
- Montero, J., Sarosiek, K. A., DeAngelo, J. D., Maertens, O., Ryan, J., Ercan, D., Piao, H., Horowitz, N. S., Berkowitz, R. S., Matulonis, U., Jänne, P. A., Amrein, P. C., Cichowski, K., Drapkin, R., & Letai, A.
- Affiliations
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Letai, Anthony
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 160
- Issue
- 5
- Pages
- 977-989
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4391197
- OpenAlex
- W2165056381
- Cited by
- 378
- References
- 35
- Citations by year
- 2026: 19 · 2025: 19 · 2024: 19 · 2023: 31 · 2022: 37 · 2021: 36 · 2020: 37 · 2019: 44 · 2018: 40 · 2017: 39 · 2016: 38 · 2015: 16
- FWCI
- 19.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (U01CA152990, K99CA188679, P01CA139980, P01CA068484, R01CA129974, R01CA135257, R21CA188858, R00CA188679)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- chemotherapy response prediction, predictive biomarkers, apoptosis signaling, drug-induced cell death, combination chemotherapy, cytotoxicity
- MeSH terms
- Carcinoma, Non-Small-Cell Lung, Cell Line, Female, Humans, Mitochondria, Neoplasms, Ovarian Neoplasms, Signal Transduction, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Cell Death, Precision Medicine
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