Autophagy as an adaptive resistance mechanism to epigenetic therapy in cancer.
- 1Division of Translational Medicine, Department of Medicine and University of Arizona Cancer Center, Tucson, AZ, United States.
- 2Division of Hematology, University of Southern California Keck School of Medicine, Los Angeles, CA, United States.
Abstract
Epigenetic therapies can reverse malignant transcriptional programs, but their activity is often constrained by adaptive stress responses that allow cancer cells to survive and recover. Autophagy is a central component of this adaptation. By sustaining metabolic homeostasis, mitochondrial fitness, proteostasis, and lysosomal recycling, autophagy can buffer the cellular injury produced by inhibitors of DNA methyltransferases, histone deacetylases, and bromodomain proteins. These observations provide a strong rationale for combining epigenetic therapies with autophagy inhibition. However, the field has too often equated autophagosome accumulation with increased autophagic flux and treatment-induced autophagy with a functional dependency. Moreover, the lysosomotropic agents used in early clinical studies incompletely inhibit autophagy and exert broader effects on lysosomal biology. Consequently, compelling preclinical activity has not translated into consistent clinical benefit. Here, we critically evaluate the mechanisms through which epigenetic therapies engage autophagy, distinguish correlative markers from causal evidence of resistance, and assess the preclinical and clinical data supporting combination strategies. We also define the major barriers to translation, including inadequate pharmacodynamic assays, a lack of predictive biomarkers, context-dependent effects on tumor and immune cells, and the limited potency and selectivity of current autophagy inhibitors. Defining when, where, and how autophagy becomes a targetable dependency will be essential to translate this compelling biology into an effective precision treatment.
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BibTeX
@article{hakim2026autophagy,
title = {{Autophagy as an adaptive resistance mechanism to epigenetic therapy in cancer.}},
author = {Natalie L Hakim and John Thomas Gialluisi and Sruthi Sureshkumar and Madison E Gamble and Claudia M Espitia and Kevin R Kelly and Jennifer S Carew and Steffan T Nawrocki},
journal = {Frontiers in oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1985943},
url = {https://europepmc.org/article/MED/42898961},
note = {CC BY},
}
RIS
TY - JOUR
TI - Autophagy as an adaptive resistance mechanism to epigenetic therapy in cancer.
AU - Natalie L Hakim
AU - John Thomas Gialluisi
AU - Sruthi Sureshkumar
AU - Madison E Gamble
AU - Claudia M Espitia
AU - Kevin R Kelly
AU - Jennifer S Carew
AU - Steffan T Nawrocki
PY - 2026
DA - 2026/10/05
JO - Frontiers in oncology
DO - 10.3389/fonc.2026.1985943
UR - https://europepmc.org/article/MED/42898961
AB - Epigenetic therapies can reverse malignant transcriptional programs, but their activity is often constrained by adaptive stress responses that allow cancer cells to survive and recover. Autophagy is a central component of this adaptation. By sustaining metabolic homeostasis, mitochondrial fitness, proteostasis, and lysosomal recycling, autophagy can buffer the cellular injury produced by inhibitors of DNA methyltransferases, histone deacetylases, and bromodomain proteins. These observations provide a strong rationale for combining epigenetic therapies with autophagy inhibition. However, the field has too often equated autophagosome accumulation with increased autophagic flux and treatment-induced autophagy with a functional dependency. Moreover, the lysosomotropic agents used in early clinical studies incompletely inhibit autophagy and exert broader effects on lysosomal biology. Consequently, compelling preclinical activity has not translated into consistent clinical benefit. Here, we critically evaluate the mechanisms through which epigenetic therapies engage autophagy, distinguish correlative markers from causal evidence of resistance, and assess the preclinical and clinical data supporting combination strategies. We also define the major barriers to translation, including inadequate pharmacodynamic assays, a lack of predictive biomarkers, context-dependent effects on tumor and immune cells, and the limited potency and selectivity of current autophagy inhibitors. Defining when, where, and how autophagy becomes a targetable dependency will be essential to translate this compelling biology into an effective precision treatment.
SN - 2234-943X
ER -