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

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.

Complete response of recurrent oral squamous cell carcinoma treated with cetuximab in combination with radiotherapy: A case series

“…We describe our experiences of three patients who received Cmab in combination with RT (Cmab + RT) for loco-regional recurrent OSCC and achieved long-term survival of 5 years or more while maintaining the QOL. We also reported PI3Kp110α findings from an immunohistochemical study to clarify the validity of our previous report (7).…”

“…Immunohistochemical staining was performed by using the EnVision method (EnVision+; Dako), as previously described (7). For the assay, specimens were obtained immediately before Cmab + RT.…”

“…Since salvage surgery may result in a significantly lower QOL, then a shift to chemoradiotherapy as the treatment strategy might be appropriate. In our previous report regarding Cmab-containing chemotherapy, we suggested that high expression of the 110-kDa catalytic subunit of class IA phosphatidylinositol 3-kinase (PI3Kp110α) may play an important role in Cmab resistance, and PI3Kp110α is a predictor for Cmab therapy in recurrent and metastatic oral squamous cell carcinoma (OSCC) (7).…”

The PI3K/Akt/mTORC signaling axis in head and neck squamous cell carcinoma: Possibilities for therapeutic interventions either as single agents or in combination with conventional therapies

“…In a study conducted on OSCC cells and xenograft model, it became evident that the abrogation of p110α catalytic subunit of PI3K using alpelisib significantly enhanced the sensitivity of the cells to cetuximab 188 . It has been also suggested that the blockage of the PI3K/Akt signaling axis may diminish the expression level of an epithelial‐mesenchymal transition‐related protein N‐cadherin, suggesting that PI3K inhibitor may reinforce the anti‐cancer property of cetuximab through suppression of cell invasion 189 . In another study, the combination of cetuximab with pan PI3K inhibitor LY294002 resulted in enhanced cytotoxicity 188 .…”

Efficacy of Providing the PI3K p110α Inhibitor BYL719 (Alpelisib) to Middle-Aged Mice in Their Diet

“…BYL719 is orally available, and in the majority of rodent studies it is administered via a once-daily oral gavage or i.p. injection [ 19 , 20 ]. However, this is not feasible for long-term aging or metabolic disease studies where treatment time may be in excess of 1 year.…”