Effects of checkpoint kinase 1 inhibition by prexasertib on the tumor immune microenvironment of head and neck squamous cell carcinoma

Abstract

Prognosis for patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) remains poor. Development of more effective and less toxic targeted therapies is necessary for HNSCC patients. Checkpoint kinase 1 (CHK1) plays a vital role in cell cycle regulation and is a promising therapeutic target in HNSCC. Prexasertib, a CHK1 inhibitor, induces DNA damage and cell death, however, its effect on the tumor immune microenvironment (TIME) is largely unknown. Therefore, we evaluated a short-term and long-term effects of prexasertib in HNSCC and its TIME. Prexasertib caused increased DNA damage and cell death in vitro and significant tumor regression and improved survival in vivo. The gene expression and multiplex immunohistochemistry (mIHC) analyses of the in vivo tumors demonstrated increased expression of genes that are related to T-cell activation and increased immune cell trafficking, and decreased expression of genes that related to immunosuppression. However, increased expression of genes related to immunosuppression emerged over time suggesting evasion of immune surveillances. These findings in gene expression analyses were confirmed using mIHC which showed differential modulation of TIME in the tumor margins and as well as cores over time. These results suggest that evasion of immune surveillance, at least in part, may contribute to the acquired resistance to prexasertib in HNSCC. K E Y W O R D S gene expression, head and neck squamous cell carcinoma (HNSCC), multiplex immunohistochemical staining, prexasertib, tumor immune microenvironment 1 | INTRODUCTION Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with a global estimate of more than 650,000 new cases and 330,000 deaths annually. 1 The common risk factors for HNSCC are the consumption of tobacco and alcohol, and human papillomavirus (HPV) infection. 2,3 Despite improvements in multimodality therapies including radiation, surgery, chemotherapy, and most recently immunotherapy, the 5-year survival rate of HNSCC patients remains poor due to its recurrence and metastasis. 4 Therefore, novel therapies are urgently needed for HNSCC.

Checkpoint kinase 1/2 inhibition potentiates anti-tumoral immune response and sensitizes gliomas to immune checkpoint blockade

“…Along these lines, type I interferon response and antigen presentation have been shown to promote anti-tumor CD8 T-cell responses 43 . Evaluation of immune-modulatory effects of the Chek1/2 inhibitor Prexasertib demonstrated an increased expression of T-cell activation related genes and decreased expression of immunosuppression-related genes in mouse head and neck squamous cell carcinoma 44 . Blosser et al identified interferon alpha and gamma response genes as gene sets associated with resistance to Prexasertib, using transcriptome analysis of a pan-cancer cell line panel, sarcoma and neuroblastoma xenograft models 45 .…”

Targeting Homologous Recombination Deficiency in Ovarian Cancer with PARP Inhibitors: Synthetic Lethal Strategies That Impact Overall Survival

“…A study combining olaparib and the CHK1 (checkpoint kinase 1) inhibitor prexasertib in a small group of patients, identified partial response in some HGSOC patients with BRCA1 mutant tumours who had demonstrated PARPi resistance [196]. Immunomodulatory effects of CHK1 inhibitors have recently been reported [197,198].…”

Tissue Multiplex Analyte Detection in Anatomic Pathology – Pathways to Clinical Implementation

“…Several recent studies have employed multiplex methods to investigate the relationship between TME and treatment efficacy as part of exploratory or retrospective analyses of tissue biopsies from clinical trial cohorts. Chaudhary et al evaluated both shortand long-term effects of prexasertib, a CHEK1 checkpoint kinase inhibitor, on TME of head and neck squamous cell carcinoma, coupling transcriptomics with multiplex mIHC (Chaudhary et al, 2021). Acutely, treated tumors demonstrated increased expression of T-cell activation and immune cell trafficking transcripts and decreased expression of immunosuppressionrelated transcripts, but over the longer time points there was an increase in immunosuppression-related transcripts suggesting evasion of immune surveillance that correlated with acquired prexasertib resistance.…”