Combinatorial functionomics identifies HDAC6-dependent molecular vulnerability of radioresistant head and neck cancer

Experimental Hematology and Oncology, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 12, 2025

Radiotherapy is the primary treatment modality for most head and neck cancers (HNCs). Despite addition of chemotherapy to radiotherapy enhance its tumoricidal effects, almost a third HNC patients suffer from locoregional relapses. Salvage therapy options such recurrences are limited often suboptimal, partly owing divergent tumor microenvironmental factors underpinning radioresistance. In this study, we utilized combinatorial functionomics approach, Quadratic Phenotypic Optimization Platform (QPOP), rationally design drug pairings that exploit molecular fingerprint vulnerability established in vitro isogenic radioresistant (RR)-HNC models. A QPOP-specific protocol was applied RR-HNC models rank compare all possible combinations 12-drug set comprising standard chemotherapy, small molecule inhibitors targeted therapies specific HNC. Drug combination efficacy evaluated by computing index scores, measuring apoptotic response. targeting validated western blot analyses, Comet assay used quantify DNA damage. Enhanced histone deacetylase inhibitor (HDACi) RR further examined vivo studies, genetic chemical inhibition major Class I/II HDACs. Regulatory roles HDAC6/SP1 axis were investigated using immunoprecipitation, gel shift ChIP-qPCR assays. Comparative transcriptomic analyses employed determine prognostic significance HDAC6. We report therapeutic potential combining panobinostat (pan-HDAC inhibitor) with AZD7762 (CHK1/2 inhibitor; AstraZeneca) or ionizing radiation (IR) re-sensitize cells showed increased damage underlying enhanced synergy. refined RR-specific prioritized HDAC6 as targetable dependency reversing provide mechanistic insights into HDAC6-mediated regulation via crosstalk involving SP1 oncogenic repair genes. From two independent patient cohorts, identified four-gene signature may have discriminative ability predict radioresistance amenable inhibition. uncovered promising should be explored treat RR-HNC.

Language: Английский

Advances in Antimicrobial Resistance and Alternative Therapy

Published: Jan. 1, 2025

Language: Английский