ON 01910.Na (rigosertib) inhibits PI3K/Akt pathway and activates oxidative stress signals in head and neck cancer cell lines
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Anil Prasad1, Nagina Khudaynazar1, Ramana V. Tantravahi2, Amanda M. Gillum2, Benjamin S. Hoffman2
1Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
2Onconova Therapeutics, Inc., Newtown, PA 18940, USA
Anil Prasad, email: email@example.com
Keywords: rigosertib, HPV, PI3K, oxidative stress, combination therapy
Received: December 10, 2015 Accepted: September 24, 2016 Published: October 15, 2016
Squamous cell carcinoma of the head and neck (HNSCC) is characterized by high morbidity and mortality. Treatment failure, drug resistance and chemoradiation toxicity have necessitated the development of alternative treatment strategies. Styryl benzyl sulfones, a family of novel small molecule inhibitors, are being evaluated as anti-neoplastic agents in multiple clinical trials. The activity of these compounds has been well characterized in several preclinical tumor studies, but their activity has yet to be fully examined in HNSCC. We tested ON 01910.Na (rigosertib), a styryl benzyl sulfone in late-stage development, in HNSCC preclinical models. Rigosertib induced cytotoxicity in both HPV(+) and HPV(-) HNSCC cells in a dose-dependent manner. Characterization of the underlying molecular mechanism indicated that rigosertib induced inhibition of the PI3K/Akt/mTOR pathway, induced oxidative stress resulting in increased generation of reactive oxygen species (ROS), and activated extracellular signal-regulated kinases (ERK1/2) and c-Jun NH2-terminal kinase (JNK). Increased phosphorylation and cytoplasmic translocation of ATF-2 were also observed following rigosertib treatment. These changes in cell signaling led us to consider combining rigosertib with HNSCC standard-of-care therapies, such as cisplatin and radiation. Our study highlights the promising preclinical activity of rigosertib in HNSCC irrespective of HPV status and provides a molecular basis for rigosertib in combination with standard of care agents for HNSCC.
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