Inhibition of platin-induced BCL2 increase overcomes chemoresistance in squamous cell carcinoma of the head and neck through resensitization to cell death

The clinical outcome of head and neck squamous cell carcinoma (HNSCC) remains poor with high recurrence rates, in part due to resistance to concurrent platinum-based chemotherapy. The anti-apoptotic BCL2 protein is involved in apoptosis resistance and tumor cell invasion/migration. Here, we test whether BCL2 overexpression predicts poor therapeutic response of HNSCC to cisplatin-based chemoradiotherapy and the effects of selective BCL2 inhibition on cisplatin-induced cell changes in vitro. BCL2 immunostatus was correlated with survival after chemoradiotherapy in a uniformly treated HNSCC cohort. The combination therapy of ABT-199, a BCL2 inhibitor, and cisplatin was evaluated in vitro using corresponding patient-derived cell lines. Colony formation and the mode of cell death were analyzed in-depth. Patients with BCL2-positive tumors (44/254) prior to treatment (either radiation, cisplatin monotherapy, or both) had shorter overall and progression-free survival (log-rank; p = 0.048) and a higher rate of tumor relapse (Fisher's exact test; p = 0.0032). BCL2 inhibition alone had no effect on cell functions in our triple panel of cisplatin-sensitive cell lines but enhanced cisplatin-induced effects. Rates of autophagy and cell death, including methuosis, were doubled, while epithelial-mesenchymal transformation was inhibited. As selective inhibition of BCL2 is available and standard of care in other malignancies, its immunohistochemical assessment could help personalize therapy by identifying a subpopulation to overcome chemoresistance, particularly in locally advanced HNSCC.