A preclinical study from the University of Pittsburgh and Magee-Womens Research Institute & Foundation identifies a two-drug strategy for killing quiescent, treatment-resistant cancer cells that can seed relapse after chemotherapy, according to a paper published August 13 in Cancer Gene Therapy.
Most cytotoxic regimens preferentially target actively dividing cells, allowing slow-cycling or non-dividing cancer cells to survive treatment and potentially drive recurrence. The problem is particularly relevant in ovarian cancer, where high initial response rates to platinum-based chemotherapy are frequently followed by relapse. The study, led by corresponding author Ronald J. Buckanovich, proposes exploiting a vulnerability created by cancer-cell quiescence rather than waiting for residual cells to resume proliferation.
Mechanism
The researchers found that downregulation of the nucleosome remodeling and deacetylase (NuRD) complex — specifically its components MBD3 and CHD4 — promotes entry into a quiescent, drug-tolerant state. Genetic knockdown of either component induced G0 arrest across ovarian cancer models. Histone deacetylase inhibitors (HDACi) phenocopied this effect pharmacologically, altering chromatin accessibility at RHO/RAC GTPase-associated loci, suppressing the MRTFA/SRF pro-proliferative transcriptional axis, and driving cells into reversible G0 arrest.
Rather than directly killing these cells, HDAC inhibition helps establish a quiescent state that creates a second vulnerability: increased dependence on proteasome and autophagy activity to maintain protein homeostasis. Combining HDACi with the proteasome inhibitor carfilzomib or the autophagy inhibitors hydroxychloroquine or chloroquine exploited that dependency and produced synergistic cell death. The HDACi-carfilzomib combination produced synergy indices of 25–73 under the highest single agent (HSA) model in vitro.
Key findings
In an ovarian cancer patient-derived xenograft (PDX) mouse model, the HDACi vorinostat (SAHA) plus carfilzomib produced greater tumor growth inhibition than either monotherapy or vehicle control across groups of 8–10 tumors.
HDACi-induced quiescence was also demonstrated in triple-negative breast cancer patient-derived organoids and breast and lung cancer cell lines, suggesting the underlying biology may extend beyond ovarian cancer. Activity was additionally evaluated in an ex vivo co-culture model incorporating primary murine hepatocytes to approximate aspects of the liver microenvironment.
Context and competition
HDAC inhibitors including vorinostat and belinostat have previously been evaluated as single agents in ovarian cancer with limited efficacy, consistent with the study's finding that HDAC inhibition can induce arrest without killing the cells. There is also clinical precedent for combining HDAC and proteasome inhibition: panobinostat plus bortezomib was previously FDA-approved for multiple myeloma, although panobinostat was subsequently withdrawn from the US market for commercial reasons. The rationale here is distinct, using HDAC inhibition to establish quiescence before exploiting the resulting proteostasis dependency.