Feedback activation of STAT3 limits the response to PI3K/AKT/mTOR inhibitors in PTEN-deficient cancer cells

Zeng-Fu Shang,Xiaoye Lv,Jianguang Zhou,Peipei Peng,Jian Wang,Haoqian Zhang,Youliang Wang,Peng Wang,Yanbo Dong,Xiutian Guo,Fang Huang,Shanhu Li,Bo Wei

doi:10.1038/s41389-020-00292-w

Zeng-Fu Shang, Xiaoye Lv + Show 11 more

Open Access

https://doi.org/10.1038/s41389-020-00292-w

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Abstract

The PI3K/AKT/mTOR signaling pathway is constitutively active in PTEN-deficient cancer cells, and its targeted inhibition has significant anti-tumor effects. However, the efficacy of targeted therapies is often limited due to drug resistance. The relevant signaling pathways in PTEN-deficient cancer cells treated with the PI3K/mTOR inhibitor BEZ235 were screened using a phosphokinase array, and further validated following treatment with multiple PI3K/AKT/mTOR inhibitors or AKT knockdown. The correlation between PTEN expression levels and STAT3 kinase phosphorylation in the tissue microarrays of gastric cancer patients was analyzed by immunohistochemistry. Cell proliferation and clonogenic assays were performed on the suitably treated PTEN-deficient cancer cells. Cytokine arrays, small molecule inhibition and knockdown assays were performed to identify related factors. PTEN-deficient tumor xenografts were established in nude mice that were treated with PI3K/AKT/mTOR and/or STAT3 inhibitors. PTEN deficiency was positively correlated with low STAT3 activity. PI3K/mTOR inhibitors increased the expression and secretion of macrophage migration inhibitory factor (MIF) and activated the JAK1/STAT3 signaling pathway. Both cancer cells and in vivo tumor xenografts showed that the combined inhibition of PI3K/AKT/mTOR and STAT3 activity enhanced the inhibitory effect of BEZ235 on the proliferation of PTEN-deficient cancer cells. Our findings provide a scientific basis for a novel treatment strategy in cancer patients with PTEN deficiency.

Highlights

The recent advances in cancer research, and identification of pro-oncogenic factors and signaling pathways have initiated a new era of precision anti-cancer treatment[1,2]
phosphatase and tensin homolog (PTEN) deficiency inhibits STAT3 activity in cancer cells Since the PI3K/AKT/mTOR signaling pathway is located at a crucial junction of multiple oncogenic signals, its inhibition activates several compensatory pathways that limit the therapeutic effects of targeted drugs
In this study, we found that PI3K/AKT/mTOR inhibitors upregulated migration inhibitory factor (MIF) expression and secretion in several PTEN-deficient cancer cells, and activated STAT3 activity through JAK1, eventually limiting the effects of these inhibitors

Summary

Introduction

The recent advances in cancer research, and identification of pro-oncogenic factors and signaling pathways have initiated a new era of precision anti-cancer treatment[1,2]. Prominent examples include epidermal growth factor receptor (EGFR) kinase inhibitors (Afatinib, Gefitinib, and Osimertinib) for treating EGFR-mutated non-small cell carcinoma (NSCLC), the abelson murine leukemia viral oncogene homolog (ABL) kinase inhibitor imatinib against chronic myelogenous leukemias harboring the BCR-ABL fusion oncogene, and BRAF inhibitors (dabrafenib and vemurafenib) for the treatment of melanoma with V600E or V600K BRAF mutations[1,3,4]. In most patients, tumors are refractory to targeted therapies (de novo resistance). Even if an initial response to targeted therapies is obtained, the vast majority of tumors subsequently become refractory (acquired resistance) and patients eventually succumb to disease progression. Several potential mechanisms of resistance against targeted therapies have been proposed using cancer cell models. One possibility is that a second mutation event in the targeted oncogene can restore its

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