Multi-Omics Identification of Genetic Alterations in Head and Neck Squamous Cell Carcinoma and Therapeutic Efficacy of HNC018 as a Novel Multi-Target Agent for c-MET/STAT3/AKT Signaling Axis

Abstract

Amongst the most prevalent malignancies worldwide, head and neck squamous cell carcinoma (HNSCC) is characterized by high morbidity and mortality. The failure of standard treatment modalities, such as surgery, radiotherapy, and chemotherapy, demands the need for in-depth understanding of the complex signaling networks involved in the development of treatment resistance. A tumor’s invasive growth and high levels of intrinsic or acquired treatment resistance are the primary causes of treatment failure. This may be a result of the presence of HNSCC’s cancer stem cells, which are known to have self-renewing capabilities that result in therapeutic resistance. Using bioinformatics methods, we discovered that elevated expressions of MET, STAT3, and AKT were associated with poor overall survival in HNSCC patients. We then evaluated the therapeutic potential of our newly synthesized small molecule HNC018 towards its potential as a novel anticancer drug. Our computer-aided structure characterization and target identification study predicted that HNC018 could target these oncogenic markers implicated in HNSCC. Subsequently, the HNC018 has demonstrated its anti-proliferative and anticancer activities towards the head and neck squamous cell carcinoma cell lines, along with displaying the stronger binding affinities towards the MET, STAT3, and AKT than the standard drug cisplatin. Reduction in the clonogenic and tumor-sphere-forming ability displays HNC018’s role in decreasing the tumorigenicity. Importantly, an vivo study has shown a significant delay in tumor growth in HNC018 alone or in combination with cisplatin-treated xenograft mice model. Collectively with our findings, HNC018 highlights the desirable properties of a drug-like candidate and could be considered as a novel small molecule for treating head and neck squamous cell carcinoma.

Recent Advances in the Targeting of Head and Neck Cancer Stem Cells

“…Another recent study by Khedkar et al identified that higher expressions of MET, STAT3, and AKT were connected with poor overall survival in HNSCC patients, so they synthesized a small molecule HNC018 that targets these molecules. HNC018 decreased sphere formation and also increased the response to cisplatin and suppressed tumor growth in vivo [141]. Another study investigating MET as a CSC therapeutic target showed that MET inhibition induces the radiosensitization of HNSCC [142].…”

Molecular pathways and targeted therapies in head and neck cancers pathogenesis

“…The MET gene is overexpressed in over 75% of HNSCC and has an increased copy number of 13%, associated with tumor progression and tumor dissemination in the early stages ( 116 ). Mutations of the MET gene are reported less frequently, but they seem to be involved in lymph node metastasis ( 117 , 118 ). HNC may also carry somatic mutations in PIK3R1 (~7%) and PTEN genes ( 51 , 119 ), with loss of function in approximately 30% of HNC (more common than other cancers) due to mutations, loss of heterozygosity in the 10q region (which includes PTEN), detected in more than 70% of HNSCC, or hypermethylation, reported in ∼5% of these.…”