PTEN Is Activated by the Addition of Cetuximab to Paclitaxel in Oral Squamous Cell Carcinoma

Abstract

Background/Aim: The mechanisms through which cetuximab (cMab) coadministration with paclitaxel (PTX) enhances antitumor efficacy remain unclear. We examined the mechanism of the antitumor enhancing effect of cMab by determining changes in gene expression in the PI3K-AKT pathway. Materials and Methods: Eight human oral squamous cell carcinoma (OSCC) cell lines were cultured three-dimensionally and exposed to PTX + cMab. The expression levels of PTEN mRNA in OSCC cell lines after anticancer drug treatment were assessed using real-time PCR. PTEN mRNA expression levels were also confirmed after administration of PTX + cMab in vivo. Western blot analysis was used to confirm the results at the protein level. Results: PTEN mRNA and protein expression were significantly increased only in the cell lines with high sensitivity to PTX + cMab, and similar results were observed in vivo. Conclusion: PTEN activation may enhance the antitumor effect of PTX + cMab.Recent studies have reported the remarkable benefits of coadministration of paclitaxel (PTX), a taxane anticancer drug, and cetuximab (cMab), an anti-human epidermal growth factor receptor (EGFR) antibody, for the treatment of recurrent/metastatic oral cancer (1). In particular, the response rate to PTX+cMab therapy has been reported to be 60% in patients whose disease had progressed after second-line treatment for platinum-refractory head and neck squamous cell carcinoma with nivolumab, an immune checkpoint inhibitor for human programmed cell death-1 (PD-1) (2). However, there are currently no clear biomarkers for predicting the effect of cMab and PTX coadministration and the mechanisms associated with the enhancement of antitumor effects.The EGFR signaling pathway, which is the pathway targeted by cMab includes the RAS signaling pathway involved in the proliferation of cancer cells and the Phosphoinositide 3-kinase (PI3K)-AKT pathway involved in the anti-apoptosis, invasion, and migration of cancer cells (3,4). The activation of the PI3K-AKT pathway starts with the phosphorylation of PI3K; subsequently, the phosphorylation of AKT promotes anti-apoptosis, invasion, and migration of cancer cells (4). Conversely, phosphatase and tensin homolog (PTEN) has been shown to inhibit cancer cell proliferation by inhibiting the PI3K-AKT pathway (5). Although many studies have shown that low PTEN expression is involved in cMab resistance (6-9), there are also reports that PTX resistance, and not just cMab resistance, is related to PTEN (10); therefore, there is a need to evaluate alterations of gene expression in the PI3K-AKT pathway including PTEN as a mechanism for the enhancement of antitumor effects with PTX+cMab. The collage gel droplet embedded culture drug sensitivity test (CD-DST) is an anticancer drug sensitivity test that combines a low-volume 3-dimensional (3D) culture, serum-free media, and an image colorimetric assay, and is effectively used to guide personalized treatment for lung, breast, gastric, and colorectal cancers (11); reportedly, it is also capable of evaluat...

Prognostic evaluation of oral squamous cell carcinoma based on pleiotrophin, urokinase plasminogen activator, and glycoprotein nonmetastatic melanoma protein B expression

“…[ 5 ] PTN expression is closely associated with tumor growth, differentiation, and metastasis. [ 6 ] GPNMB is a type I transmembrane glycoprotein that mediates intracellular signaling pathways and participates in cellular growth, proliferation, and differentiation; its abnormal expression is related to the pathological and physiological processes of various diseases. [ 7 ] Urokinase plasminogen activator (uPA) is a serine proteolytic enzyme that can specifically dissolve proteins in the extracellular matrix and basement membrane, enabling tumor cells to break through the barrier formed by connective tissue after detachment from the primary lesion and grow locally infiltratively, leading to distant metastasis into the vascular system or lumen.…”