Phosphorylation of PI3K regulatory subunit p85 contributes to resistance against PI3K inhibitors in radioresistant head and neck cancer

Oral Oncology
Myung Woul HanSang Yoon Kim

Abstract

PI3K/Akt/mTOR pathway is commonly activated in most cancers and is correlated with resistance to anticancer therapies such as radiotherapy. Therefore, PI3K is an attractive target for treating PI3K-associated cancers. We investigated the basal expression and the expression after treatment of PI3K inhibitor or Src inhibitor of PI3K/Akt pathway-related proteins in AMC-HN3, AMC-HN3R, HN30 and HN31 cells by performing immunoblotting analysis. The sensitivity to PI3K inhibitors or Src inhibitor was analyzed by MTT assay and clonogenic assay. To determine the antitumoral activity of combination treatment with PI3K inhibitor and Src inhibitor, we used using xenograft mouse model. We found that PI3K regulatory subunit p85 was predominantly phosphorylated in radioresistant head and neck cancer cell line (HN31), which showed resistance to PI3K inhibitors. Next, we investigated mechanism through which PI3K p85 phosphorylation modulated response to PI3K inhibitors. Of note, constitutive activation of Src was found in HN31 cells and upon PI3K inhibitor treatment, restoration of p-Src was occurred. Src inhibitor improved the efficacy of PI3K inhibitor treatment and suppressed the reactivation of both Src and PI3K p85 in HN31 cells. Furthermo...Continue Reading

Citations

Feb 21, 2019·Molecular Cancer·Jing YangXiawei Wei
Oct 4, 2019·European Journal of Medicinal Chemistry·Fatma M ElmenierKhaled A M Abouzid
Apr 19, 2021·Critical Reviews in Oncology/hematology·Silvia Rita VitalePaolo Vigneri
Dec 28, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Fatma M ElmenierKhaled A M Abouzid

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