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.