In silico repurposing of midostaurin as a therapeutic candidate for head and neck cancer via targeting SPARC/MMP9/CD44 Cancer-Associated Fibroblasts (CAFs) oncogenic signature

Kuan-Chou Lin; Chia-Che Wu; Ntlotlang Mokgautsi; Bashir Lawal; Ching-Zong Wu; Alexander Th Wu; Yung-Kang Shen; Ming-Che Liu

In silico repurposing of midostaurin as a therapeutic candidate for head and neck cancer via targeting SPARC/MMP9/CD44 Cancer-Associated Fibroblasts (CAFs) oncogenic signature

Am J Cancer Res. 2023 Mar 15;13(3):1004-1025. eCollection 2023.

Authors

Kuan-Chou Lin^{1

2

3}, Chia-Che Wu^{4

5}, Ntlotlang Mokgautsi^{6

7}, Bashir Lawal⁸, Ching-Zong Wu³, Alexander Th Wu^{9

10}, Yung-Kang Shen¹¹, Ming-Che Liu^{11

12

13

14

10}

Affiliations

¹ Division of Oral and Maxillofacial Surgery, Department of Dentistry, Wan Fang Hospital, Taipei Medical University Taipei 11031, Taiwan.
² Division of Oral and Maxillofacial Surgery, Department of Dentistry, Shin Kong Wu Ho-Su Memorial Hospital Taipei, Taiwan.
³ School of Dentistry, College of Oral Medicine, Taipei Medical University Taipei 11031, Taiwan.
⁴ Taipei Medical University, School of Medicine, Department of Otorhinolaryngology Taipei 11031, Taiwan.
⁵ Taipei Medical University, Wang Fang Hospital, Department of Otorhinolaryngology Taipei 11031, Taiwan.
⁶ Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica Taipei 11031, Taiwan.
⁷ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
⁸ Department of Pathology, University of Pittsburgh Pittsburgh, PA 15232, USA.
⁹ The PhD Program of Translational Medicine, College of Medical Science and Technology, Taipei Medical University Taipei 11031, Taiwan.
¹⁰ Clinical Research Center, Taipei Medical University Hospital Taipei 11031, Taiwan.
¹¹ School of Dental Technology, College of oral Medicine, Taipei Medical University Taipei 11031, Taiwan.
¹² Department of Urology, Taipei Medical University Hospital Taipei 11031, Taiwan.
¹³ Graduate Institute of Clinical Medicine, School of Medicine, College of Medicine, Taipei Medical University Taipei 11031, Taiwan.
¹⁴ TMU Research Center of Urology and Kidney, Taipei Medical University Taipei 11031,Taiwan.

PMID: 37034220
PMCID: PMC10077027

Abstract

Head and neck squamous carcinoma (HNSCC) affects more than half a million individuals and ranks the ninth leading cause of death globally each year. Many patients develop treatment resistance leading to poor clinical outcomes. The poor treatment responses are in part due to the heterogeneity of HNSCC tumor and tumor microenvironment (TME). The interaction of tumor cells with their TME has been studied vigorously in recent years because of their pivotal roles in tumorigenesis and determining the treatment response. Cancer-associated fibroblasts (CAFs) are one of the most abundant tumor-infiltrating cells, which have been shown to associate with the aggressive behavior of HNSCC. Hence, targeting and disrupting the tumor-CAFs interactions represents a rational therapeutic approach. To develop targeted therapeutic drugs against CAFs, the identification of CAF-associated gene signature is essential. Here, we analyzed multiple sequencing databases including microarrays and single-cell RNA-sequencing databases and identified SPARC/MMP9/CD44 as HNSCC targetable gene signatures encompassing cancer-associated fibroblasts (CAFs). We found SPARC/MMP9CD44 signature was highly expressed in HNSC tissues compared to adjacent normal tissues. Increased SPARC/MMP9/CD44 signature levels strongly correlated with tumor-infiltrating CAFs, suggesting the functional importance of this signature for HNSCC-CAFs interaction and progression. Subsequently, we utilized a genomics approach and identified midostaurin as the top-ranking drug candidate for targeting SPARC/MMP9/CD44 signature. For validation, we performed molecular docking of midostaurin in complex with SPARC/MMP9/CD44 and demonstrated midostaurin's high binding affinities compared to their respective standard inhibitors. In summary, our study provided a rapid genomics approach for identifying targetable gene signature and drug candidate for HNSCC.

Keywords: Head and neck squamous cancers (HNSCC); cancer-associated fibroblasts (CAFs); drug resistance; midostaurin; molecular docking.