Abstract 1136: MK-1775, a selective wee1 kinase inhibitor, overcomes cisplatin resistance associated with high risk TP53 mutations in squamous cell carcinoma of the head and neck.
Authors: Osman Abdullah A. 
Published: August 2014

Abstract
Head and neck squamous cell carcinoma (HNSCC) affects over 500,000 patients worldwide annually and over half this number of patients dies from the disease each year. Platinum-based chemotherapy is currently employed in the treatment of advanced HNSCC to decrease distant metastasis and to improve local-regional control through sensitization of external beam radiation. Platinum based agents have been shown to be less effective in the context of specific genomic events such as mutation of TP53 tumor suppressor gene. Recent data from whole-exome sequencing of HNSCC reveals that this gene is mutated in 60-80% of HNSCC. It is unclear whether all mutations in TP53 equally trigger an aggressive HNSCC phenotype which is resistant to platinum based agents. Therefore, we have developed an algorithm termed Evolutionary Gradient and Structure (EGS) which stratifies HNSCC patients based on the type of TP53 mutation and correlates the score (high risk vs. low risk) with clinical outcomes. Based on this system, twelve isogenic cell lines harboring different p53 mutants were created in a p53 null HNSCC cell line background. Cells expressing high risk TP53 mutations were highly resistant to cisplatin relative to wildtype TP53. Decreased cisplatin sensitivity associated with these mutations was found to be driven by their inability to undergo cellular senescence, the primary mechanism of death for cells with wildtype TP53. It has been previously shown that tumors expressing mutant TP53 rely more heavily on activation of the S- and G2-phase checkpoints for mediating the growth arrest needed to repair DNA damage and survive genotoxic stress, making these cells potentially sensitive to G2 checkpoint inhibitors. Wee1 is a tyrosine kinase that has been linked to DNA damage induced G2 arrest, owing to its ability to inactivate cyclin dependent kinase 1 (CDK1)) through phosphorylation of the Tyr15 residue. Recent studies have shown that inhibitors of Wee1 sensitize TP53 mutant colon cancer tumors to cisplatin in preclinical models by abrogating a G2 arrest. Therefore, we assessed the ability of the wee1 kinase inhibitor, MK-1775, to sensitize the HNSCC cells to cisplatin. Treatment of HNSCC cell lines expressing high risk TP53 mutations with MK-1775 and cisplatin resulted in strong synergism with a combination index of 0.07. Furthermore, the addition of MK-1775 to cisplatin did not restore induction of senescence, but rather resulted in increased cell death through mitotic catastrophe. This study demonstrates the potential for a therapeutic strategy aimed at tumors expressing high risk TP53 mutations. Through the use of synthetic lethality it appears possible to restore cell death pathways and improve treatment outcomes in pre-clinical models of aggressive HNSCC.
Citation Format: Abdullah A. Osman. MK-1775, a selective wee1 kinase inhibitor, overcomes cisplatin resistance associated with high risk TP53 mutations in squamous cell carcinoma of the head and neck. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1136. doi:10.1158/1538-7445.AM2013-1136