ON 01910.Na (rigosertib) inhibits PI3K/Akt pathway and activates oxidative stress signals in head and neck cancer cell lines

Squamous cell carcinoma of the head and neck (HNSCC) is associated with high morbidity and mortality, with treatment failure, drug resistance, and chemoradiation toxicity driving the need for alternative therapeutic strategies. Styryl benzyl sulfones, a novel class of small-molecule inhibitors, are under investigation as anti-neoplastic agents in multiple clinical trials. While these compounds have demonstrated efficacy in various preclinical tumor models, their activity in HNSCC remains underexplored.
In this study, we evaluated ON 01910.Na (rigosertib), a styryl benzyl sulfone in late-stage development, using preclinical HNSCC models. Rigosertib induced dose-dependent cytotoxicity in both HPV-positive and HPV-negative HNSCC cells. Mechanistic analysis revealed that rigosertib inhibited the PI3K/Akt/mTOR pathway, induced oxidative stress ON-01910 with increased reactive oxygen species (ROS) generation, and activated extracellular signal-regulated kinases (ERK1/2) and c-Jun NH2-terminal kinase (JNK). Additionally, rigosertib treatment led to increased phosphorylation and cytoplasmic translocation of ATF-2.
These signaling alterations provided a rationale for exploring rigosertib in combination with standard HNSCC therapies, including cisplatin and radiation. Our findings underscore the potential of rigosertib as a therapeutic option for HNSCC, regardless of HPV status, and support its further investigation in combination treatment strategies.