TY - JOUR
T1 - 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
AU - Khedkar, Harshita Nivrutti
AU - Chen, Lung Ching
AU - Kuo, Yu Cheng
AU - Wu, Alexander T.H.
AU - Huang, Hsu Shan
N1 - Funding Information:
The National Science and Technology Council, Taiwan, grant number NSTC111-2314-B-038-017, the Ministry of Science and Technology, Taiwan, grant number MOST111-2314-B-038-122, and the Shin Kong Wu Ho-Su Memorial Hospital SKH-TMU-112-02 awarded to H.-S. Huang. ATH Wu is also funded by The National Science and Technology Council, Taiwan, grant numbers 111-2314-B-038-098 and 111-2314-B-038-142.
Funding Information:
The NCI Developmental Therapeutics Program (DTP) for the 60 cancer cell-line screening of selected compounds described in this paper was funded by the National Cancer Institute, National Institutes of Health (NIH-NCI).
Publisher Copyright:
© 2023 by the authors.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
KW - bioinformatics
KW - drug resistance
KW - drug-likeness
KW - head and neck squamous cell carcinoma
KW - molecular docking
KW - multi-target therapeutics
KW - target-based structure discovery
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U2 - 10.3390/ijms241210247
DO - 10.3390/ijms241210247
M3 - Article
C2 - 37373393
AN - SCOPUS:85164027396
SN - 1661-6596
VL - 24
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 12
M1 - 10247
ER -
