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Anti-invasive effects of CXCR4 and FAK inhibitors in non-small cell lung carcinomas with mutually inactivated p53 and PTEN tumor suppressors

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Summary

Non-small cell lung carcinoma (NSCLC) is the most common type of lung cancer. At the time of diagnosis, a large percentage of NSCLC patients have already developed metastasis, responsible for extremely high mortality rates. CXCR4 receptor and focal adhesion kinase (FAK) are known to regulate such invasive cancer behavior. Their expression is downregulated by p53 and PTEN tumor suppressors which are commonly co-inactivated in NSCLC patients and contribute to metastasis. Therefore, targeting CXCR4 or FAK seems to be a promising strategy in suppressing metastatic spread of p53/PTEN deficient NSCLCs. In this study, we first examined the invasive characteristics of NSCLC cells with suppressed p53 and PTEN activity using wound healing, gelatin degradation and invasion assays. Further, changes in the expression of CXCR4 and FAK were evaluated by RT-qPCR and Western Blot analysis. Finally, we tested the ability of CXCR4 and FAK inhibitors (WZ811 and PF-573228, respectively) to suppress the migratory and invasive potential of p53/PTEN deficient NSCLC cells, in vitro and in vivo using metastatic models of human NSCLC. Our results showed that cells with mutually inactive p53 and PTEN have significantly increased invasive potential associated with hyperactivation of CXCR4 and FAK signaling pathways. Treatments with WZ811 and PF-573228 inhibitors significantly reduced migratory and invasive capacity in vitro and showed a trend of improved survival in vivo. Accordingly, we demonstrated that p53/PTEN deficient NSCLCs have extremely invasive phenotype and provided a rationale for the use of CXCR4 or FAK inhibitors for the suppression of NSCLC dissemination.

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Authors and Affiliations

  1. Department of Neurobiology, University of Belgrade, Institute for Biological Research “Sinisa Stankovic”, Bulevar Despota Stefana 142, Belgrade, 11060, Serbia

    Miodrag Dragoj, Jasna Bankovic, Sofija Jovanovic Stojanov, Milica Pesic & Tijana Stankovic

  2. Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, 41110, Larissa, Greece

    Evangelia Sereti & Konstantinos Dimas

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  1. Miodrag Dragoj
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  2. Jasna Bankovic
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  3. Evangelia Sereti
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  4. Sofija Jovanovic Stojanov
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  7. Tijana Stankovic
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Correspondence to Tijana Stankovic.

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The authors declare no conflict of interest.

Funding

This study was supported by the Ministry of Education, Science and Technological Development of the Republic of Serbia (Grant Nos III41031 and 173020), COST Action CM1106 “Chemical Approaches to Targeting Drug Resistance in Cancer Stem Cells” and COST Action CM1407 “Challenging organic syntheses inspired by nature - from natural products chemistry to drug discovery”.

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This article does not contain any studies with human participants performed by any of the authors.

All animal procedures were in compliance with Directive (2010/63/EU) on the protection of animals used for experimental and other scientific purposes and was approved by the IACUC and the local Directorate-General for Regional Rural Economy and Veterinary (Licence No 5542/228006).

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Dragoj, M., Bankovic, J., Sereti, E. et al. Anti-invasive effects of CXCR4 and FAK inhibitors in non-small cell lung carcinomas with mutually inactivated p53 and PTEN tumor suppressors. Invest New Drugs 35, 718–732 (2017). https://doi.org/10.1007/s10637-017-0494-4

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