Abstract 4441
Background
In this study we evaluated potential of targeting CXCR4 and focal adhesion kinase (FAK) in suppressing metastatic spread of p53/PTEN deficient non-small cell lung carcinomas (NSCLCs).
Methods
We first examined the invasive characteristics of NSCLC cells with suppressed p53 and PTEN activity using wound healing, gelatin degradation and invasion assays. Namely, NCI-H460 cells with applied pharmacological inhibition of wild type p53 and PTEN activity (NCI-H460p53-/PTEN-) were analyzed along with COR-L23 cells that have intrinsically inactive both tumor suppressors. 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 orthotropic metastatic lung carcinoma mouse model.
Results
Our results showed that cells with mutually inactive p53 and PTEN have significantly increased migratory and invasive potential. Such invasive phenotype is associated with hyperactivation of CXCR4 and FAK and their downstream AKT and ERK signaling pathways. Treatments with WZ811 and PF-573228 significantly reduced migratory and invasive capacity of NCI-H460p53-/PTEN- and COR-L23 cells that was accompanied by the downregulation of AKT signaling. In addition, these two inhibitors showed trend to improve survival of SCID mice with orthotopicaly inoculated COR-L23 cells that extensively invaded lung parenchyma and developed distant metastases compared to NCI-H460 derived tumors.
Conclusions
Overall, 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.
Clinical trial identification
Legal entity responsible for the study
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”.
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”.
Disclosure
All authors have declared no conflicts of interest.