Phosphatidyl inositol-3 kinase (<i>PIK3CA</i>) E545K mutation confers cisplatin resistance and a migratory phenotype in cervical cancer cells

Arjumand, Wani; Merry, Cole; Wang, Chen; Saba, Elias; McIntyre, John B.; Kornaga, Elizabeth; Ghatage, Prafull; Doll, Corinne; Lees‐Miller, Susan P.

doi:10.18632/oncotarget.10955

Cited by 34 publications

(30 citation statements)

References 49 publications

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“…For example, ADAM17-induced chemoresistance drug resistance in hepatocellular carcinoma cells [19]and RLIP76-induced drug resistance in pancreatic cancer cells [20]were regulated by PI3K/AKT pathway. Numerous studies have confirmed that PI3K/AKT can confer resistance to DDP-based treatment in cervical cancer[21, 22], lung cancer[22], and ovarian cancer[23]. In our study, four genes involved in this pathway, including NFKB1 , PPP2R5B , PPP2R2B , and CCNE2 , were significantly deregulated in the cisplatin-resistant cell line.…”

Section: Discussionsupporting

confidence: 74%

Transcriptome Sequencing Reveals Key Pathways and Genes Associated with Cisplatin Resistance in Lung Adenocarcinoma A549 Cells

Fang

Zhang

et al. 2017

PLoS ONE

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Acquired resistance to cisplatin-based chemotherapy frequently occurs in patients with non-small cell lung cancer, and the underlying molecular mechanisms are not well understood. The aim of this study was to investigate whether a distinct gene expression pattern is associated with acquired resistance to cisplatin in human lung adenocarcinoma. Whole-transcriptome sequencing was performed to compare the genome-wide gene expression patterns of the human lung adenocarcinoma A549 cisplatin-resistant cell line A549/DDP with those of its progenitor cell line A549. A total of 1214 differentially expressed genes (DEGs) were identified, 656 of which were upregulated and 558 were downregulated. Functional annotation of the DEGs in the Kyoto Encyclopedia of Genes and Genomes database revealed that most of the identified genes were enriched in the PI3K/AKT, mitogen-activated protein kinase, actin cytoskeleton regulation, and focal adhesion pathways in A549/DDP cells. These results support previous studies demonstrating that the pathways regulating cell proliferation and invasion confer resistance to chemotherapy. Furthermore, the results proved that cell adhesion and cytoskeleton regulation is associated with cisplatin resistance in human lung cancer. Our study provides new promising biomarkers for lung cancer prognosis and potential therapeutic targets for lung cancer treatment.

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Section: Discussionsupporting

confidence: 74%

Transcriptome Sequencing Reveals Key Pathways and Genes Associated with Cisplatin Resistance in Lung Adenocarcinoma A549 Cells

Fang

Zhang

et al. 2017

PLoS ONE

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“…The activation of PI3K/AKT pathway was reported to contribute to cisplatin and gemcitabine resistance, both of which are currently the frontline choice for advanced bladder cancer (15,42,43). Arjumand et al (15) suggested that cervical cancer cells engineered with a PIK3CA E545K mutation were more resistant to cisplatin.…”

Section: Discussionmentioning

confidence: 99%

“…Arjumand et al (15) suggested that cervical cancer cells engineered with a PIK3CA E545K mutation were more resistant to cisplatin. Previously, we observed that PDX BL0269 with a PIK3CA -H1047R mutation showed resistance to both cisplatin and gemcitabine (5).…”

Section: Discussionmentioning

confidence: 99%

“…Pictilisib, also known as GDC-0941, is an oral class I pan-PI3K inhibitor with activity in the nanomolar range against all class I PI3K isoforms. Pictilisib binds to the ATP-binding pocket of PI3K p110, prevents activation of PI3K and formation of PIP3, and phosphorylation of downstream targets such as AKT (14,15). Pictilisib is now in advanced stages of clinical trials (16–18).…”

Section: Introductionmentioning

confidence: 99%

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The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer

Zeng

Zhu

Hong

et al. 2017

Clinical Cancer Research

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Purpose Activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action and resistant mechanisms of drugs targeting the PI3K pathway. Experimental Design Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine. Potential predictive biomarkers for pictilisib were evaluated and RNA-sequencing was performed to explore drug resistance mechanisms. Results The bladder cancer cell line TCCSUP, which harbors a PIK3CA E545K mutation, was sensitive to pictilisib compared to cell lines with wild type PIK3CA. Pictilisib exhibited stronger anti-tumor activity in bladder cancer PDX models with PI3KCA H1047R mutation or amplification than control PDX model. Pictilisib synergized with cisplatin and/or gemcitabine in vitro, significantly delayed tumor growth and prolonged survival compared with single drug treatment in the PDX models. The phosphorylation of ribosomal protein S6 correlated with response to pictilisib both in vitro and in vivo, and could potentially serve as biomarker to predict response to pictilisib. Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance. Conclusion These preclinical results provide new insights into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer.

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“…This suggests that targeting the PI3K/Akt pathway in cervical cancers that harbour PIK3CA activating mutations, such as E545K, may have therapeutic benefit due to inhibition of NFκB/IL-6 signalling and paracrine STAT3 activation. Indeed, it has recently been demonstrated that the PIK3CA E545K mutant confers resistance to cisplatin, suggesting that a combination treatment of cisplatin and a PI3K inhibitor may have synergistic effects in cervical cancer [66].…”

Section: Discussionmentioning

confidence: 99%

Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Akt - NF?B - IL-6 signalling axis

Morgan

Macdonald

2018

Preprint

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Persistent human papillomavirus (HPV) infection is the leading cause of cervical cancer. Although the fundamental link between HPV infection and oncogenesis is established, the specific mechanisms of virus-mediated transformation remain poorly understood. We previously demonstrated that the HPV encoded E6 protein increases the activity of the proto-oncogenic transcription factor STAT3 in primary human keratinocytes; however, the molecular basis for STAT3 activation in cervical cancer remains unclear. Here, we show that STAT3 phosphorylation in HPV positive cervical cancer cells is mediated primarily via autocrine activation by the pro-inflammatory cytokine Interleukin 6 (IL-6). Antibody-mediated blockade of IL-6 signalling in HPV positive cells inhibits STAT3 phosphorylation, whereas both recombinant IL-6 and conditioned media from HPV positive cells leads to increased STAT3 phosphorylation within HPV negative cervical cancer cells. Interestingly, we demonstrate that non-conventional activation of the transcription factor NF?B, involving the protein kinase Akt, is required for IL-6 production and subsequent STAT3 activation. Our data provides new insights into the molecular re-wiring of cancer cells by HPV E6. We reveal that activation of an IL-6 signalling axis drives the autocrine and paracrine phosphorylation of STAT3 within HPV positive cervical cancers cells. Greater understanding of this pathway provides a potential opportunity for the use of existing clinically approved drugs for the treatment of HPV-mediated cervical cancer.

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Phosphatidyl inositol-3 kinase (PIK3CA) E545K mutation confers cisplatin resistance and a migratory phenotype in cervical cancer cells

Cited by 34 publications

References 49 publications

Transcriptome Sequencing Reveals Key Pathways and Genes Associated with Cisplatin Resistance in Lung Adenocarcinoma A549 Cells

Transcriptome Sequencing Reveals Key Pathways and Genes Associated with Cisplatin Resistance in Lung Adenocarcinoma A549 Cells

The Phosphatidylinositol 3-Kinase Pathway as a Potential Therapeutic Target in Bladder Cancer

Autocrine STAT3 activation in HPV positive cervical cancer through a virus-driven Akt - NF?B - IL-6 signalling axis

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