Biology subjects

Gewirtz, D.

Publications and source records attributed to Gewirtz, D..

2 recordsLinked to original sources

bioRxiv2026

Sacituzumab Govitecan as an Effective Strategy for Sensitizing Chemoresistant HNSCC Cells to Senolytic Intervention

Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer worldwide and is marked by a high tumor relapse due to acquired chemoresistance, requiring alternative strategies to sensitize resistant tumors to treatment. Sacituzumab govitecan (SG), a TROP2-targeting antibody-drug conjugate, has been successful in limiting tumor progression in pretreated patients with triple-negative and hormone-receptor positive HER2-negative breast cancer. However, it has been ineffective as a monotherapy in HNSCC. This may be attributed to the promotion of senescence ultimately leading to tumor relapse. We established that isogenic cisplatin-sensitive and -resistant HNSCC cells undergo senescence following SG treatment. Senolytics have been effective in sensitizing solid tumors to standard of care chemotherapies in preclinical studies. Consequently, we investigated the effectiveness of SG treatment followed by the senolytic, ABT-263, as a two-hit therapeutic strategy against cisplatin-resistant HNSCC. SG followed by ABT-263 sensitized HNSCC cells to apoptosis via a BAK and BAX-dependent mechanism. In vivo studies confirmed that SG treatment followed by ABT-263 limited tumor progression and extended survival without notable toxicity. Thus, SG in combination with senolytic treatment may be an effective strategy for overcoming not only cisplatin-resistance but also SG resistance via targeting the senescent cell population.

cancer biology↗

bioRxiv2017

Reversibility of chemotherapy-induced senescence is independent of autophagy and a potential model for tumor dormancy and cancer recurrence.

Autophagy and senescence are both well-established responses to chemotherapy and radiation that often occur in parallel, contributing to growth arrest in tumor cells. However, it has not been established whether this growth arrest is reversible. This question was addressed using non-small cell lung cancer models exposed to the cancer chemotherapeutic drug, etoposide. Senescent cells that were sorted, identified by {beta}-galactosidase staining and alterations in morphology, isolated by flow cytometric cell sorting based on C12FDG staining, and real-time live microscopy were found to be capable of recovering proliferative capacity. Autophagy, monitored by vacuole formation, SQSTM1/p62 degradation, and LC3BII generation did not interfere with either the senescence arrest or proliferative recovery and was nonprotective in function (i.e. autophagy inhibition via both pharmacological and genetic strategies had negligible impact on the response to etoposide).\n\nThese observations argue against the premise that (chemotherapy-induced) senescence is irreversible and indicate that therapy-induced senescence may ultimately be a transient process in that at least a subpopulation of tumor cells can and will remain metabolically active and recover proliferative capacity independently of autophagic turnover. We therefore propose that dormant tumor cells may be capable of prolonged survival in a state of autophagy/senescence and that disease recurrence may reflect escape from this senescence-arrested state.

cancer biology↗