Hnc0014, a multi-targeted small-molecule, inhibits head and neck squamous cell carcinoma by suppressing c-met/stat3/cd44/pd-l1 oncoimmune signature and eliciting antitumor immune responses

Jih Chin Lee, Alexander T.H. Wu, Jia Hong Chen, Wen Yen Huang, Bashir Lawal, Ntlotlang Mokgautsi, Hsu Shan Huang, Ching Liang Ho

Research output: Contribution to journalArticlepeer-review

Abstract

Despite advancements in diagnostic and standard treatment modalities, including surgery, radiotherapy, and chemotherapy, overall survival rates of advanced-stage head and neck squamous cell carcinoma (HNSCC) patients have remained stagnant for over three decades. Failure of these treatment modalities, coupled with post-therapy complications, underscores the need for alternative interventions and an in-depth understanding of the complex signaling networks involved in developing treatment resistance. Using bioinformatics tools, we identified an increased expression of c-Met, STAT3, and CD44 corresponding to a poor prognosis and malignant phenotype of HNSCC. Subsequently, we showed that tumorsphere-derived exosomes promoted cisplatin (CDDP) resistance and colony and tumorsphere formation in parental HNSCC cells, accompanied by an increased level of oncogenic/immune evasive markers, namely, c-Met, STAT3, CD44, and PD-L1. We then evaluated the therapeutic potential of a new small molecule, HNC0014. The molecular docking analysis suggested strong interactions between HNC0014 and oncogenic molecules; c-Met, STAT3, CD44, and PD-L1. Subsequently, we demonstrated that HNC0014 treatment suppressed HNSCC tumorigenic and expression of stemness markers; HNC0014 also reduced cancer-associated fibroblast (CAF) transformation by Exosp-and CAF-induced tumorigenic properties. HNC0014 treatment alone suppressed tumor growth in a cisplatin-resistant (SAS tumorspheres) mouse xenograft model and with higher inhibitory efficacy when combined with CDDP. More importantly, HNC0014 treatment significantly delayed tumor growth in a syngeneic mouse HNSCC model, elicited an antitumor immune profile, and reduced the total c-Met, STAT3, and their phosphorylated forms, PD-L1 and CD44, contents in serum exosomes. Collectively, our findings provide supports for HNC0014 as a multi-targeted immunotherapeutic lead compound for further development.

Original languageEnglish
Article number3759
Pages (from-to)1-18
Number of pages18
JournalCancers
Volume12
Issue number12
DOIs
Publication statusPublished - Dec 2020

Keywords

  • C-Met/STAT3/CD44/PD-L1 signaling
  • Cancer-associated fibroblast (CAF)
  • Cisplatin resistance
  • Head and neck squamous carcinoma (HNSCC)
  • Small-molecule immunotherapeutic drug
  • Tumorsphere-derived exosomes (Exo)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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