Selective inhibition of PI3K110α as a novel therapeutic strategy for cetuximab‑resistant oral squamous cell carcinoma

Tsuchihashi,Hiroki; Naruse,Tomofumi; Yanamoto,Souichi; Okuyama,Kohei; Furukawa,Kohei; Omori,Keisuke; Umeda,Masahiro

doi:10.3892/or.2020.7674

Selective inhibition of PI3K110α as a novel therapeutic strategy for cetuximab‑resistant oral squamous cell carcinoma

Authors:
- Hiroki Tsuchihashi
- Tomofumi Naruse
- Souichi Yanamoto
- Kohei Okuyama
- Kohei Furukawa
- Keisuke Omori
- Masahiro Umeda
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Affiliations: Department of Clinical Oral Oncology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852‑8588, Japan
Published online on: July 7, 2020 https://doi.org/10.3892/or.2020.7674
Pages: 863-872
Copyright: © Tsuchihashi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

High expression of the 110 kDa catalytic subunit of the class IA PI3K (PI3Kp110α) may play an important role in cetuximab resistance exhibited by both colorectal cancer and head and neck squamous cell carcinoma. Therefore, the present study aimed to examine the association between the expression of proteins in the PI3Kp110α pathway and cetuximab resistance, and the antitumor effects of alpelisib (PI3K inhibitor) and cetuximab in oral squamous cell carcinoma (OSCC) cells. The association between PI3Kp110α protein expression levels and the tumor response to cetuximab was determined using immunohistochemistry. OSCC cells were treated with alpelisib, cetuximab, or in combination, and the effects were examined in vitro and in vivo. PI3Kp110α protein expression was significantly associated with the tumor response to cetuximab (P<0.05) and 1‑year progression‑free survival and overall survival (P<0.05). Combined treatment of alpelisib and cetuximab resulted in enhanced antitumor effects in vitro compared with either agent administered alone. In particular, the expression level of N‑cadherin, an epithelial‑mesenchymal transition‑related protein, was decreased, suggesting that the invasion potential of cetuximab‑resistant cells decreased. Furthermore, the expression of proteins in the PI3K pathway were decreased in tumors from mice with OSCC xenografts treated with alpelisib and cetuximab in combination. These results indicate that novel regimens of systemic therapy (such as chemotherapy), with combinations of cetuximab and alpelisib, may be beneficial for patients with cetuximab‑resistant OSCC.

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