Related Experiment Video
Updated: Apr 27, 2026
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
CIP2A mediates erlotinib-induced apoptosis in non-small cell lung cancer cells without EGFR mutation
Cheng-Yi Wang1, Ting-Ting Chao2, Fang-Yu Chang2
1Department of Internal Medicine, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 23148, Taiwan; Medical Research Center, Cardinal Tien Hospital, School of Medicine, Fu Jen Catholic University, New Taipei City 23148, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan.
Background:
Epidermal growth factor receptor (EGFR) inhibitors show favorable clinical response in some patients with non-small cell lung cancer (NSCLC) who have no EGFR mutation, indicating alternative mechanisms for their tumoricidal effects. We previously showed erlotinib, a selective EGFR antagonist, inhibited the growth of sensitive hepatocellular carcinoma cells by inhibiting the cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. The aim of this study was to determine if erlotinib can also inhibit the growth of NSCLC cells by inactivating the CIP2A-dependent signaling pathway.
Methods:
Four NSCLC cell lines (H358 H441 H460 and A549) were treated with erlotinib to determine their sensitivity to erlotinib-induced cell death and apoptosis. Expression of CIP2A and the downstream AKT were analyzed. The effects of CIP2A on erlotinib-induced apoptosis were confirmed by overexpression of CIP2A and knockdown of CIP2A gene expression in the sensitive cells and resistant cells, respectively. In vivo efficacy of erlotinib against H358 xenograft tumor was also determined in nude mice.
Results:
Erlotinib induced significant cell death and apoptosis in H358 and H441 cells, as evidenced by increased caspase 3 activity and cleavage of pro-caspase 9 and PARP, but not in H460 or A549 cells. The apoptotic effect of erlotinib in the sensitive H358 cells was associated with downregulation of CIP2A, increase in PP2A activity and decrease in AKT phosphorylation. Overexpression of CIP2A and AKT protected the sensitive H358 cells from erlotinib-induced apoptosis. Knockdown of CIP2A gene expression by siRNA enhanced the erlotinib-induced apoptotic in the resistant H460 cells that resembled the sensitive H358 cells. Erlotinib also inhibited the growth of H358 tumors in nude mice.
Conclusions:
The CIP2A-dependent pathway mediates the tumoricidal effects of erlotinib on NSCLC cells without EGFR mutations in vitro and in vivo. CIP2A may be a novel molecular target against NSCLC for future drug development.
Insights
Erlotinib, an EGFR inhibitor, effectively kills non-small cell lung cancer (NSCLC) cells lacking EGFR mutations by targeting the CIP2A pathway. This study highlights CIP2A as a potential therapeutic target for NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Epidermal growth factor receptor (EGFR) inhibitors show efficacy in some non-small cell lung cancer (NSCLC) patients without EGFR mutations.
- Erlotinib, an EGFR antagonist, previously inhibited hepatocellular carcinoma cell growth by targeting the cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway.
- Investigating erlotinib's mechanism in NSCLC without EGFR mutations is crucial for understanding alternative therapeutic strategies.
Purpose of the Study:
- To determine if erlotinib inhibits non-small cell lung cancer (NSCLC) cell growth by inactivating the CIP2A-dependent signaling pathway.
- To elucidate the role of CIP2A in erlotinib's tumoricidal effects in NSCLC.
- To evaluate erlotinib's efficacy in preclinical NSCLC models.
Main Methods:
- Treatment of four NSCLC cell lines (H358, H441, H460, A549) with erlotinib to assess sensitivity to cell death and apoptosis.
- Analysis of CIP2A and AKT expression levels.
- Confirmation of CIP2A's role via gene overexpression and knockdown experiments.
- In vivo assessment of erlotinib efficacy in H358 xenograft models.
Main Results:
- Erlotinib induced significant apoptosis in H358 and H441 NSCLC cells, associated with CIP2A downregulation and increased PP2A activity.
- Overexpression of CIP2A and AKT conferred resistance to erlotinib-induced apoptosis in sensitive cells.
- Knockdown of CIP2A enhanced erlotinib-induced apoptosis in resistant H460 cells.
- Erlotinib demonstrated in vivo efficacy against H358 NSCLC xenografts.
Conclusions:
- The CIP2A-dependent pathway mediates erlotinib's tumoricidal effects in EGFR-mutation-negative NSCLC cells.
- CIP2A inactivation is a key mechanism for erlotinib's efficacy in this NSCLC subset.
- CIP2A represents a promising molecular target for developing novel NSCLC therapies.
More Related Videos
09:38Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
08:52Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Related Concept Videos
02:38Mitogens and the Cell Cycle
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
01:31The Intrinsic Apoptotic Pathway
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...