Efficacy of PP121 in primary and metastatic non-small cell lung cancers

Abstract

Tyrosi ne ki nase i nhibitors are a cl i nical ly standard treatment option for non-small cell lung cancers (NSCLCs), the leading cause of cancer-related deaths in the US. These targeted agents include first, second and third generation tyrosine kinase inhibitors; however, these lack clinical efficacy in the treatment of NSCLC due to i nt ri nsic and acqui red resist ance. This resist ance may be a result of genetic aberrations in oncogenic signaling mediators of divergent pathways. The present study aimed to i nvest igat e a novel dual t yrosi ne ki nase and PI3K inhibitor, PP121, as a targeted agent in NSCLC cell lines. The present study co-cultured PP121 with healthy human astrocytes, a prevalent cell type located in the brain of NSCLC brain metastases. To date, few preclinical studies have examined the efficacy of PP121 as an anticancer agent, and to the best of my knowledge, no previous studies have previously evaluated its therapeutic potential in the treatment of NSCLC. To investigate the clinical heterogeneity of NSCLC, patient-derived adenocarcinoma (ADC) and squamous cell carcinoma (SCC) xenograft models were used, which exhibited epidermal growth factor receptor (EGFR) mutations and mesenchymal-epithelial transition (MET) factor amplifications. Not ably, both EGFR and MET are known contributors to tyrosine kinase inhibitor resistance; thus, the aforementioned mutations and amplifications enabled the effects of PP121 to be evaluated in these solid tumors. In addition, a co-cultured model system using both NSCLC cells and astrocytes was employed to assess the effects of PP121 on the invasion of ADC and SCC cells in a multicellular environment. Results of the present study demonstrated that PP121 exerted an antitumorigenic effect in the aforementioned model systems via downregulation of pharmacodynamic targets.