efatutazone and Lung-Neoplasms

AIB1Δ4 is an N-terminally truncated isoform of the oncogene amplified in breast cancer 1 (AIB1) with increased expression in high-grade human ductal carcinoma

Topics: Animals; Cell Culture Techniques, Three Dimensional; Cell Line, Tumor; CRISPR-Cas Systems; Dexamethasone; Disease Progression; Electric Impedance; Enhancer Elements, Genetic; Female; Humans; Lung Neoplasms; Mice; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Nuclear Receptor Coactivator 3; Phenotype; Protein Isoforms; Receptors, Glucocorticoid; RNA Splicing; Signal Transduction; Thiazolidinediones; Triple Negative Breast Neoplasms; Zebrafish

Development of acquired resistance to EGFR-TKI therapy continues to be a serious clinical problem in Lung adenocarcinoma management. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists demonstrate anti-tumor activity likely via transactivating genes that regulate cell proliferation, differentiation and apoptosis. Efatutazone, a novel later generation PPARγ agonist, selectively activates PPARγ target genes and has antiproliferative effects in a range of malignancies. However, the exact function and molecular mechanism of PPARγ agonists efatutazone in EGFR-TKI gefitinib-resistance of Lung adenocarcinoma has not been determined. In this study, we studied the development of acquired resistance to an EGFR-TKI gefitinib in lung adenocarcinoma cells and investigated the antiproliferative effects of efatutazone in the acquired resistant cells. The treatment of gefitinib-resistant cells with efatutazone reduced the growth of gefitinib-resistant cells in a dose- and time-dependent manner, and facilitated the anti-proliferative effects of gefitinib. Mechanistic investigations suggested that efatutazone acted by upregulating protein expression of PPARγ, phosphatase and tensin homolog (PTEN), inactivating the Akt pathway, followed by dephosphorylation of p21Cip1 at Thr145 without affecting the transcriptional levels. Our results suggested that efatutazone, alone or in combination with gefitinib, might offer therapeutic effects in lung adenocarcinoma.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; Gefitinib; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; PPAR gamma; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Quinazolines; Signal Transduction; Survival Analysis; Thiazolidinediones

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are effective for non-small cell lung cancers (NSCLC) with EGFR-activating mutations. However, most responders develop resistance. Efatutazone, a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is currently under clinical evaluation; it has antiproliferative effects and induces cellular morphological changes and differentiation. The present study investigated the effects of efatutazone in EGFR-TKI-resistant NSCLC cells, while focusing on cell motility. The PC-9-derived NSCLC cell lines PC-9ER and PC-9ZD, resistant to EGFR-TKI due to v-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) amplification-induced phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT) activation and an EGFR T790M mutation, respectively, were used. These cells exhibit enhanced cell motility due to transforming growth factor β (TGF-β)/Smad2 family member 2 (Smad2) pathway activation. Efatutazone had no growth-inhibitory effect on the tested cells but inhibited the motility of EGFR-TKI-resistant cells in wound closure and transwell assays. Efatutazone plus erlotinib treatment provided greater inhibition of PC-9ER cell migration than efatutazone or erlotinib alone. Efatutazone suppressed increased TGF-β2 secretion from both cell lines (shown by ELISA) and downregulation of TGF-β2 transcription (observed by quantitative RT-PCR). Immunoblot analysis and luciferase assays revealed that efatutazone suppressed Smad2 phosphorylation and its transcriptional activity. These results suggest that efatutazone inhibits cell motility by antagonizing the TGF-β/Smad2 pathway and effectively prevents metastasis in NSCLC patients with acquired resistance to EGFR-TKI regardless of the resistance mechanism.

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Differentiation; Cell Line, Tumor; Cell Movement; Cell Proliferation; Down-Regulation; Drug Resistance, Neoplasm; Enzyme Activation; Epidermal Growth Factor; ErbB Receptors; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Phosphatidylinositol 3-Kinases; PPAR gamma; Protein Kinase Inhibitors; Quinazolines; Smad2 Protein; Thiazolidinediones; Transforming Growth Factor beta2; Wound Healing