BH3 profiling analyses for functional precision medicine.
6 affiliations
- 1Proteomics and proteostasis Laboratory, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain. [email protected].
- 2Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain. [email protected].
- 3Cell biology, Intracellular compartments and Cancer, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. [email protected].
- 4Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universitat de Barcelona, Barcelona, Spain. [email protected].
- 5Cell biology, Intracellular compartments and Cancer, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. [email protected].
- 6Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain. [email protected].
Abstract
Evasion of apoptosis is a central hallmark of cancer and a major driver of therapeutic resistance. While genomic and transcriptomic profiling have reshaped our understanding of cancer, they often fail to predict whether a cell will die when treated. BH3 profiling and its variants solve this by directly interrogating mitochondrial apoptotic priming and its reliance on anti-apoptotic dependencies by directly exposing cells to defined BH3-only peptides. Over the past decade, researchers have successfully applied these assays across a wide range of hematologic malignancies, solid tumors, and resistant cancer models. This functional assay predicts treatment response, identifies rational drug combinations, and reveals mechanisms of both intrinsic and acquired resistance to apoptosis. In hematologic malignancies, functional dependence on BCL-2 measured by BH3 profiling strongly correlates with sensitivity to venetoclax, while reduced mitochondrial priming underlies resistance. In solid tumors, these analyses have uncovered previously unappreciated reliance on BCL-xL and MCL-1, enabling the design of effective combination strategies despite limited single-agent activity of BH3 mimetics. Recent methodological advances, including high-throughput and dynamic BH3 profiling, further highlight the changing and heterogeneous nature of apoptotic regulation within tumors. This review evaluates the preclinical and early clinical evidence for BH3 profiling in precision oncology. Beyond assessing its current performance, we examine the methodological requirements for its transition into clinical settings and its potential to address the limitations of current personalized cancer therapies.
Related
- The role of gene regulatory evolution in weapon diversification: Insights from comparative genomics, chromatin profiling, and functional analyses of BMP signaling in horned beetles
- Advancing clinical precision medicine via peripheral blood immune single‐cell omics
- Metal Hypersensitivity in Total Joint Arthroplasty: Molecular Immunopathogenesis, Diagnostic Controversies, and Prospects for Precision Medicine
- Exosomes in regenerative medicine from biological messengers to engineered nanocarriers for precision therapeutics
- Nucleic Acid Therapeutics in Rare Disease: From Precision Medicine to Programmable Platforms.
BibTeX
@article{moralessanchez2026profiling,
title = {{BH3 profiling analyses for functional precision medicine.}},
author = {Paula Morales-Sánchez and Joan Montero},
journal = {Oncogenesis},
year = {2026},
month = jul,
doi = {10.1038/s41389-026-00647-9},
url = {https://europepmc.org/article/MED/42901888},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - BH3 profiling analyses for functional precision medicine.
AU - Paula Morales-Sánchez
AU - Joan Montero
PY - 2026
DA - 2026/07/01
JO - Oncogenesis
DO - 10.1038/s41389-026-00647-9
UR - https://europepmc.org/article/MED/42901888
AB - Evasion of apoptosis is a central hallmark of cancer and a major driver of therapeutic resistance. While genomic and transcriptomic profiling have reshaped our understanding of cancer, they often fail to predict whether a cell will die when treated. BH3 profiling and its variants solve this by directly interrogating mitochondrial apoptotic priming and its reliance on anti-apoptotic dependencies by directly exposing cells to defined BH3-only peptides. Over the past decade, researchers have successfully applied these assays across a wide range of hematologic malignancies, solid tumors, and resistant cancer models. This functional assay predicts treatment response, identifies rational drug combinations, and reveals mechanisms of both intrinsic and acquired resistance to apoptosis. In hematologic malignancies, functional dependence on BCL-2 measured by BH3 profiling strongly correlates with sensitivity to venetoclax, while reduced mitochondrial priming underlies resistance. In solid tumors, these analyses have uncovered previously unappreciated reliance on BCL-xL and MCL-1, enabling the design of effective combination strategies despite limited single-agent activity of BH3 mimetics. Recent methodological advances, including high-throughput and dynamic BH3 profiling, further highlight the changing and heterogeneous nature of apoptotic regulation within tumors. This review evaluates the preclinical and early clinical evidence for BH3 profiling in precision oncology. Beyond assessing its current performance, we examine the methodological requirements for its transition into clinical settings and its potential to address the limitations of current personalized cancer therapies.
SN - 2157-9024
ER -