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Published on: March 7, 2025
Targeted Therapy of HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy between
Ourania N Kostopoulou1, Mark Zupancic1,2, Mariona Pont1
1Department of Oncology-Pathology, Karolinska Institute, Karolinska University Hospital, 171 64 Stockholm, Sweden.
Abstract:
Human papillomavirus positive (HPV+) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC) have a favorable outcome, but upon relapse, survival is poor and new therapeutical options are needed. Recently, we found synergistic effects by combining the food and drug administration approved (FDA) phosphoinositide 3-kinase (PI3K) and fibroblast-growth-factor-receptor (FGFR) inhibitors BYL719 and JNJ-42756493 on TSCC cell lines. Here this approach was extended and Cyclin-Dependent-Kinase-4/6 (CDK4/6) and Poly-ADP-ribose-polymerase (PARP) and WEE1 inhibitors PD-0332991, and MK-1775 respectively were also examined. HPV+ CU-OP-2, -3, -20, and HPV- CU-OP-17 TSCC cell lines were treated with either BYL719 and JNJ-42756493, PD-0332991 BMN-673 and MK-1775 alone or in different combinations. Viability, proliferation, and cytotoxicity were followed by WST-1 assays and the IncuCyte S3 Live® Cell Analysis System. All inhibitors presented dose-dependent inhibitory effects on tested TSCC lines. Synergy was frequently obtained when combining CDK4/6 with PI3K inhibitors, but only sometimes or rarely when combining CDK4/6 with FGFR inhibitors or PARP with WEE1 inhibitors. To conclude, using CDK4/6 with PI3K or FGFR inhibitors, especially PD-0332991 with BYL719 presented synergy and enhanced the decrease of viability considerably, while although dose dependent responses were obtained with PARP and WEE1 inhibitors (BMN-673 and MK-1775 resp.), synergy was rarely disclosed.
Insights
Combining cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with phosphoinositide 3-kinase (PI3K) or fibroblast growth factor receptor (FGFR) inhibitors shows synergistic effects in human papillomavirus-positive tonsillar squamous cell carcinoma. This combination therapy enhances cell viability reduction, offering new therapeutic options for this cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Human papillomavirus-positive (HPV+) tonsillar and base of tongue squamous cell carcinoma (TSCC/BOTSCC) typically have a favorable prognosis.
- Relapsed HPV+ TSCC/BOTSCC exhibits poor survival, necessitating novel therapeutic strategies.
- Previous research indicated synergistic effects between phosphoinositide 3-kinase (PI3K) and fibroblast growth factor receptor (FGFR) inhibitors in TSCC cell lines.
Purpose of the Study:
- To extend the investigation of synergistic drug combinations for HPV+ TSCC/BOTSCC.
- To evaluate the efficacy of combining Cyclin-Dependent Kinase 4/6 (CDK4/6), Poly-ADP-ribose-polymerase (PARP), and WEE1 inhibitors with PI3K and FGFR inhibitors.
- To identify optimal drug combinations that enhance cytotoxicity and reduce viability in TSCC cell lines.
Main Methods:
- Utilized HPV+ (CU-OP-2, -3, -20) and HPV- (CU-OP-17) TSCC cell lines.
- Treated cell lines with individual and combined inhibitors: BYL719 (PI3K), JNJ-42756493 (FGFR), PD-0332991 (CDK4/6), BMN-673 (PARP), and MK-1775 (WEE1).
- Assessed cell viability, proliferation, and cytotoxicity using WST-1 assays and the IncuCyte S3 Live® Cell Analysis System.
Main Results:
- All tested inhibitors demonstrated dose-dependent inhibitory effects on TSCC cell lines.
- Synergistic effects were frequently observed when combining CDK4/6 inhibitors with PI3K inhibitors.
- Combinations of CDK4/6 with FGFR inhibitors, and PARP with WEE1 inhibitors showed synergy less frequently.
- The combination of PD-0332991 (CDK4/6) with BYL719 (PI3K) significantly enhanced the reduction in cell viability.
Conclusions:
- Combining CDK4/6 inhibitors with PI3K or FGFR inhibitors, particularly PD-0332991 and BYL719, demonstrates significant synergy in TSCC.
- These combinations substantially enhance the decrease in cell viability, suggesting a promising therapeutic approach.
- While PARP and WEE1 inhibitors showed dose-dependent effects, synergy was rarely observed in combination studies.
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