Downregulation of ATM and BRCA1 Predicts Poor Outcome in Head and Neck Cancer: Implications for ATM-Targeted Therapy

Abstract

ATM and BRCA1 are DNA repair genes that play a central role in homologous recombination repair. Alterations of ATM and BRCA1 gene expression are found in cancers, some of which are correlated with treatment response and patient outcome. However, the role of ATM and BRCA1 gene expression in head and neck cancer (HNC) is not well characterized. Here, we examined the prognostic role of ATM and BRCA1 expression in two HNC cohorts with and without betel quid (BQ) exposure. The results showed that the expression of ATM and BRCA1 was downregulated in BQ-associated HNC, as the BQ ingredient arecoline could suppress the expression of both genes. Low expression of either ATM or BRCA1 was correlated with poor overall survival (OS) and was an independent prognostic factor in multivariate analysis (ATM HR: 1.895, p = 0.041; BRCA1 HR: 2.163, p = 0.040). The combination of ATM and BRCA1 expression states further improved on the prediction of OS (HR: 4.195, p = 0.001, both low vs. both high expression). Transcriptomic analysis showed that inhibition of ATM kinase by KU55933 induced apoptosis signaling and potentiated cisplatin-induced cytotoxicity. These data unveil poor prognosis in the HNC patient subgroup with low expression of ATM and BRCA1 and support the notion of ATM-targeted therapy.

ATM Inhibition-Induced ISG15/IFI27/OASL Is Correlated with Immunotherapy Response and Inflamed Immunophenotype

“…Previously, we found that the ATM inhibitor (ATMi) KU55933 activated interferon pathways in cancer cells (Figure 2A) [29]. Here, gene expression profiling and GSEA demonstrated that KU55933 also induced the interferon response in CDDP-R cancer cells (Figure 2B).…”

“…Total RNA from KU55933-treated HEp-2 (10 µM, 24 h) and HB8 (10 and 20 µM, 24 h) cells was harvested using Tri-reagent (Sigma) for the analysis of gene expression profiles (Human OneArray Plus HOA 7.1, Phalanx Biotech, Taiwan), as described in our paper [29]. Transcriptome data sets of normal human dermal fibroblasts treated with KU60019 and lung cancer cells resistant to cisplatin were retrieved from NCBI GEO with accession numbers GSE178115 and GSE21656, respectively.…”

“…Total RNA was converted to cDNA using the High-Capacity cDNA Archive Kit (Applied Biosystems, Foster City, CA, USA). The resulting cDNA was used for qPCR in the StepOne System (Applied Biosystems) as described [29]. The qPCR results were examined by dissociation (melting) curve analysis to ensure the specificity of qPCR products.…”

Arecoline Is Associated With Inhibition of Cuproptosis and Proliferation of Cancer-Associated Fibroblasts in Oral Squamous Cell Carcinoma: A Potential Mechanism for Tumor Metastasis

“…It was found that the expression of DNA repair genes ATM and BRCA1 was suppressed in betel nut-associated HNSCC due to arecoline. Low expression of either ATM or BRCA1 was related to poor overall survival and presented as an independent prognostic factor ( 31 ). Here, for the first time, we screened thirteen DEGs based on arecoline-related OSCC samples from the GSE139869 gene array and TCGA-OSCC dataset.…”

Targeting DNA damage response as a potential therapeutic strategy for head and neck squamous cell carcinoma

“…Another key mechanism by which ATM and ATR inhibitors selectively enhance tumor cell inactivation when combined with IR) may be through the inducing of senescence (142). A recent study showed that the ATM inhibitor KU55933 induces apoptotic signaling and potentiates cisplatin-induced cytotoxicity (45). GSK63541A, a novel ATM inhibitor, has been shown to have a highly selective radiosensitization activity that is superior to cisplatin and cetuximab (115).…”