Polo-Like Kinase 1 Inactivation Enhances PI3K Inhibition-Mediated Apoptosis of NOTCH1-Mutant Head and Neck Squamous Cell Carcinoma

Authors

• Pooja A Shah
• Tuhina Mazumdar
• Soma Ghosh
• Lacin Yapindi
• Reid T Powell
• Yong S Park
• Li Shen
• Anne M Fernandez
• Clifford C Stephan
• Jing Wang
• Andrew G Sikora
• Jawad Kazi
• Mitchell J Frederick
• Faye M Johnson

Language

English

Publication Date

8-10-2025

Journal

Cancer Letters

DOI

10.1016/j.canlet.2025.217814

PMID

40412794

PMCID

PMC13524226

PubMedCentral® Posted Date

8-29-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

PI3K inhibition causes apoptosis selectively in NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC), but modest single-agent responses and acquired resistance (AR) limit the clinical efficacy of targeted agents. To address these limitations, we investigated novel combination therapies. We tested the efficacy of 5768 compounds as single agents and 139 in combination with PI3K inhibitors in sensitive and AR NOTCH1-mutant HNSCC cell lines. We generated synergy/efficacy classifications for the combinations using multiple metrics of statistical drug synergy and growth rate indices. The PLK1/PI3K combination's efficacy was validated using orthogonal in vitro methods and in two HNSCC xenograft models. Compound efficacy was enriched in 30 of 306 drug classes. Drugs from nine classes enhanced the cell killing of PI3K inhibition. We pursued experiments with PLK1 inhibitors based on clinical relevance and efficacy in parental and AR models. The combination of PLK1 and PI3K inhibition caused apoptosis, DNA damage, and immunogenic cell death in vitro and extended survival in vivo. PLK1 activity decreased following PI3K inhibition only in sensitive NOTCH1-mutant HNSCC cell lines and not in AR or resistant wild-type cells. The combination of PI3K and PLK1 inhibition causes robust killing of HNSCC and overcomes PI3K inhibitor resistance. Specific and well-tolerated PI3K and PLK1 inhibitors that do not have overlapping toxicity are in clinical development. We hypothesize that this combination may have a wide therapeutic window with significant efficacy but modest toxicity because it should spare normal cells that have wild-type NOTCH1 and are not sensitive to PI3K inhibition.

Keywords

Humans, Receptor, Notch1, Polo-Like Kinase 1, Apoptosis, Animals, Squamous Cell Carcinoma of Head and Neck, Protein Serine-Threonine Kinases, Cell Line, Tumor, Phosphoinositide-3 Kinase Inhibitors, Xenograft Model Antitumor Assays, Cell Cycle Proteins, Head and Neck Neoplasms, Mutation, Proto-Oncogene Proteins, Carcinoma, Squamous Cell, Drug Synergism, Mice, Protein Kinase Inhibitors, Antineoplastic Combined Chemotherapy Protocols, Drug Resistance, Neoplasm, Mice, Nude, Signal Transduction, NOTCH1, head and neck squamous cell carcinoma, PI3K, Polo-like kinase 1

Published Open-Access

yes

Recommended Citation

Shah, Pooja A; Mazumdar, Tuhina; Ghosh, Soma; et al., "Polo-Like Kinase 1 Inactivation Enhances PI3K Inhibition-Mediated Apoptosis of NOTCH1-Mutant Head and Neck Squamous Cell Carcinoma" (2025). Children’s Nutrition Research Center Staff Publications. 427.
https://digitalcommons.library.tmc.edu/staff_pub/427