Targeted Therapy of HPV Positive and Negative Tonsillar Squamous Cell Carcinoma Cell Lines Reveals Synergy between CDK4/6, PI3K and Sometimes FGFR Inhibitors, but Rarely between PARP and WEE1 Inhibitors

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.

Impaired DNA double-strand break repair and effective radiosensitization of HPV-negative HNSCC cell lines through combined inhibition of PARP and Wee1

“…Numerically, the cell numbers after dual inhibition in HSC4 and UT-SCC-60a reached only 74.3% and 64.5% of the numbers calculated for a strictly additive growth inhibition and we cannot rule out that some synergy may exist. But as these data do not provide a clear hint for a general and prominent effect in HNSCC cells, in line with a recent report [25] , this was not investigated in detail.

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Efficacy of combined targeted therapy with PI3K and CDK4/6 or PARP and WEE1 inhibitors in neuroblastoma cell lines

“…This may be because SK-N-SH cell line was sensitive and lacked mutated p53 and it was difficult to observe further decreases in viability upon combination treatment, especially with doses that induced effects in more resistant cell lines. Our previous study showed that when combining PI3K and FGFR inhibitors in NB, MB and head and neck cancer cell lines, effects in cell lines that were particularly sensitive to one of the drugs were not observed ( 10 – 13 , 40 , 42 ). It is unknown why combining PD-0332991 + BYL719 resulted in enhanced inhibition in SK-N-AS, SK-N-BE(2)-C, SK-N-DZ and SK-N-FI, however all four cell lines have mutated p53.…”

Special Issue “HPV in the Head and Neck Region 2.0”

“…Recently, we presented a Special Issue on “HPV in the head and neck region” which included several contributions to the overall knowledge of HPV in the head and neck region. In this second “Special Issue on HPV in the head and neck region 2.0”, eight original articles, one review, and one systematic review are presented [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ].…”

“…An eighth original article described attempts to experimentally use various targeted therapies for HPV+ and HPV− tonsillar and base tongue cancer [ 8 ]. The authors used 4 cell lines of which three were HPV+ and one HPV-.…”

“…The authors used 4 cell lines of which three were HPV+ and one HPV-. The study using various targeted therapies showed that especially combining the CDK4/6 inhibitor PD-0332991 with the PI3K inhibitor BYL719 presented synergy and enhanced the decrease in viability considerably, while although dose-dependent responses were obtained with PARP and WEE1 inhibitors (BMN-673 and MK-1775, respectively), synergy was rarely disclosed [ 8 ].…”