Since NOXA is capable of binding and inhibiting the anti-apoptotic protein MCL-1, we hypothesized whether (1) NOXA expression alone could induce cell death in HNSCC cells; (2) a combination of NOXA expression and the BCL-2/BCL-XL inhibitor ABT-263 could synergistically induce cell death; (3) a retinoid analogue fenretinide that induces the ATF3/ATF4-NOXA pathway could be an alternative for NOXA expression and the combination with ABT-263 efficiently induces cell death. This evidence concerns the gene ATF3 and head and neck squamous cell carcinoma.