TD-19, an Erlotinib Derivative, Induces Epidermal Growth Factor Receptor Wild-Type Nonsmall-Cell Lung Cancer Apoptosis through CIP2A-Mediated Pathway

Abstract

Some patients with nonsmall-cell lung cancer (NSCLC) without epidermal growth factor receptor (EGFR) mutations still respond to gefitinib and erlotinib, suggesting that there may be a mechanism(s) other than the EGFR pathway that mediates the tumoricidal effects. In the current study, we tested the efficacy of TD-19, a novel compound chemically modified from erlotinib, which has more potent apoptotic effects than erlotinib in EGFR wild-type NSCLC cell lines. TD-19 induced significant cell death and apoptosis in H358, H441, H460, and A549 cells, as evidenced by increased caspase-3 activity and cleavage of procaspase-9 and poly (ADP-ribose) polymerase. The apoptotic effect of TD-19 in H460 cells, which were resistant to erlotinib, was associated with downregulation of cancerous inhibitor of protein phosphatase 2A (CIP2A), increased protein phosphatase 2A (PP2A) activity, and decreased AKT phosphorylation, but minimal effects on EGFR phosphorylation. Overexpression of CIP2A partially protected the H460 cells from TD-19-induced apoptosis. Okadaic acid, a known PP2A inhibitor, significantly reduced TD-19-induced apoptosis, while forskolin, which increased PP2A activity, increased the apoptotic effect of TD-19. TD-19 inhibited the growth of H460 xenograft tumors by ∼80%. We conclude that TD-19 exerted tumoricidal effects on NSCLC cells. TD-19 provides proof that the CIP2A pathway may be a novel target for the treatment of EGFR wild-type NSCLC.

MicroRNA-383-5p acts as a prognostic marker and inhibitor of cell proliferation in lung adenocarcinoma by cancerous inhibitor of protein phosphatase 2A

“…Furthermore, CIP2A status was a significant prognostic factor for patients with non-small cell carcinoma, and CIP2A protein expression levels were revealed to be overexpressed in human lung cancer samples and associated with poor survival rates ( 33 ). Previous studies have provided direct evidence that CIP2A may promote cell proliferation via the protein kinase B signaling pathway and protect the non-small cell lung cancer cells from apoptosis ( 34 , 35 ). These results imply an oncogenic role for CIP2A.…”

A single quantum dot-based biosensor for DNA point mutation assay

“…The H460 is a wild-type lung cancer cell without L858R point mutation. 39,40 We used the pure buffer solution and the genomic DNA without any targets as the control group. As shown in Fig.…”

Gefitinib induces non‑small cell lung cancer H1650 cell apoptosis through downregulating tumor necrosis factor‑related apoptosis‑inducing ligand expression levels

“…As with other types of cancer, chemotherapy, radiotherapy and surgery serve critical roles in the treatment of NSCLC. However, the aforementioned methods are associated with various disadvantages and insufficiencies (7)(8)(9). Radiotherapy has been demonstrated to have the best curative effect for NSCLC (10).…”