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

Abstract

Tyrosine kinase inhibitors are a clinically 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 intrinsic and acquired resistance. This resistance may be a result of genetic aberrations in oncogenic signaling mediators of divergent pathways. The present study aimed to investigate a novel dual tyrosine kinase 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. Notably, 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.

PP121, a dual inhibitor of tyrosine and phosphoinositide kinases, relieves airway hyperresponsiveness, mucus hypersecretion and inflammation in a murine asthma model

“…PP121 is a dual inhibitor of tyrosine kinase and phosphoinositide kinases, and its antitumor properties have been identified in esophageal cancer, prostate cancer and hepatocellular carcinoma (Peng et al 2015 ; Bello, et al 2021 ; Zhai et al 2021 ). Recently, PP121 has been shown to exert an antitumorigenic effect in primary and metastatic non-small cell lung cancers (NSCLC) (Quick 2023 ). However, the role of PP121 in asthma is still unclear.…”