Abstract
Oral cavity squamous cell carcinomas (OSCCs) are aggressive tumors, and their recurrence leads to poor prognosis and reduced survival rates. This study aimed to identify therapeutic targets and to evaluate the efficacy of targeted inhibitors in OSCC patient-derived xenograft (PDX) models. Herein, we reported that OSCC PDXs recapitulated the genomic signatures of their paired primary tumors and the expression of CHEK1, PIK3CA, and PIK3CD was significantly upregulated in OSCC. The antitumor efficacy of CHK1 inhibitors (PF477736, AZD7762, LY2606368) and PI3K inhibitors (BYL719, GDC0941, GSK1059615) was investigated in OSCC cell lines and PDX models. Targeting either CHK1 or PI3K effectively inhibited cell proliferation and colony formation by inducing cell cycle arrest and apoptosis in in vitro cell-based assays. Cisplatin-based chemotherapy combined with CHK1 inhibitor treatment synergistically inhibited cell proliferation by suppressing CHK1 phosphorylation and inducing PARP cleavage. Furthermore, compared with monotherapy, cotreatment with CHK1 and PI3K inhibitors exerted synergistic anticancer effects by suppressing CHK1, AKT, and 4E-BP1 phosphorylation. In summary, our study identified CHK1 and PI3K as promising targets, especially in a dual treatment strategy combining a CHK1 inhibitor with cisplatin or a PI3K inhibitor as a novel therapeutic approach for OSCC patients with aberrant cell cycle regulation and PI3K signaling activation.
Highlights
Oral cavity squamous cell carcinoma (OSCC) is an aggressive tumor and is the most common malignancy of the oral cavity, accounting for up to 90% of all malignant neoplasms of the oral cavity [1,2,3].The incidence of Oral cavity squamous cell carcinomas (OSCCs) appears to be increasing worldwide, especially in Asia, and this common cancer is the fourth most prevalent cancer among males in Taiwan [4,5]
We demonstrate that checkpoint kinase 1 (CHEK1), PIK3CA, and PIK3CD are significantly upregulated in OSCC and provide evidence that a dual treatment strategy that combine a CHK1 inhibitor with a phosphoinositide 3-kinase (PI3K) inhibitor or cisplatin is a potential therapeutic option for patients
To evaluate the tumor-associated biological pathways and seek potential druggable targets in OSCC, the mutational landscape and tumor transcriptome profiles of the tumors from these patients and the paired xenografts were determined by whole-exome sequencing and RNA sequencing (RNA-seq), respectively
Summary
Oral cavity squamous cell carcinoma (OSCC) is an aggressive tumor and is the most common malignancy of the oral cavity, accounting for up to 90% of all malignant neoplasms of the oral cavity [1,2,3]. The incidence of OSCC appears to be increasing worldwide, especially in Asia, and this common cancer is the fourth most prevalent cancer among males in Taiwan [4,5]. The current treatment for OSCC patients is surgical excision at an early stage, with subsequent chemotherapy or radiotherapy. Postoperative concurrent chemoradiotherapy is an acceptable standard therapy for patients at high risk of recurrence, as determined by pathological examination [11].
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