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Objectives: 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. Material and Methods: 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. Results: 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. Furthermore, downregulation of PI3K p85 expression by using a specific siRNA suppressed Src phosphorylation. Conclusions: Together, our results imply the novel role of the PI3K regulatory subunit p85 in the development of resistance to PI3K inhibitors and suggest the presence of a regulatory loop between PI3K p85 and Src in radioresistant head and neck cancers with constitutively active PI3K/Akt pathway.