Abstract 5465: The molecular basis of activity of rigosertib (ON 01910.Na) in head and neck cancer cell lines
Authors: Prasad Anil , Khudaynazar Nagina , Kuzontkoski Paula M. , Tantravahi Ramana V. , Gillum Amanda M. 
Published: May 2015

Head and neck cancer is a major global health problem, and squamous cell carcinoma (HNSCC) is its most common subtype. Alcohol and tobacco use are classic risk factors; however, human papillomavirus (HPV) is associated with the fastest expanding HNSCC subgroup. Conventional therapies (surgery, radiation and platinum-based chemotherapy) for both HPV(+) and HPV(-) HNSCC are of limited efficacy, and are often accompanied by significant, adverse side effects and acquired drug resistance. We aim to develop novel HNSCC therapeutics to overcome these limitations. Rigosertib sodium (ON 01910.Na) is a novel benzyl styryl sulfone inhibitor of the PI3K and PLK pathways, and has shown efficacy in the treatment of myelodysplastic syndromes. We evaluated the effects of rigosertib on the HPV(-) HNSCC cell lines, FaDu, Detroit 562 and UM-SCC-1, and on the HPV(+) HNSCC cell line, UM-SCC-47. We found that rigosertib was cytotoxic to both HPV(+) and HPV(-) HNSCC cells in a dose-dependent manner. Analyzing the potential molecular mechanisms responsible for rigosertib-induced effects, we observed inhibition of both the PI3K/Akt/mTOR and growth factor receptor pathways. We also found that rigosertib inhibited the expression and activation of several cell cycle regulators, including the cyclin dependent kinases, CDK2 and CDK4, and CDC2. Reactive oxygen species (ROS) and the activation of Extracellular Signal-Regulated Kinases 1 and 2 (ERK1/2) and c-Jun NH2-terminal Kinase (JNK) increased, likely due to cellular stress induced by blocking the aforementioned signaling pathways. Rigosertib treatment resulted in decreased levels of the pro-survival Mcl-1 protein, and enhanced phosphorylation of c-Jun and Activating Transcription Factor 2 (ATF-2). Rigosertib treatment also resulted in caspase 3 and 9 cleavage, molecular hallmarks of apoptosis. Microarray analysis of rigosertib-treated FaDu cells revealed high levels of TNFAIP3/A20 expression. TNFAIP3/A20 is a tumor suppressor whose reintroduction into null lymphoma cell lines has been shown to induce apoptosis. Rigosertib-treated cells also showed decreased expression of CYP1B1 (a component of the cytochrome P450 system), which plays a key role in drug resistance to several conventional chemotherapeutics. Finally, we analyzed the effects of rigosertib plus cisplatin on the survival of the HPV(-) HNSCC cell lines, FaDu and Detroit 562, and found a significant combinatorial benefit. In summary, rigosertib mediates apoptosis in HNSCC cells by altering multiple signal transduction, survival and cell-cycle control pathways. These data suggest that rigosertib may be an effective treatment for HNSCC as a single agent or in combination with other chemotherapeutics. A Phase 2 trial of rigosertib in patients with HNSCC has recently opened.

Citation Format: Anil Prasad, Nagina Khudaynazar, Paula M. Kuzontkoski, Ramana V. Tantravahi, Amanda M. Gillum. The molecular basis of activity of rigosertib (ON 01910.Na) in head and neck cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5465. doi:10.1158/1538-7445.AM2014-5465