Dual inhibition of MEK1/2 and EGFR synergistically induces caspase-3-dependent apoptosis in EGFR inhibitor-resistant lung cancer cells via BIM upregulation

  title={Dual inhibition of MEK1/2 and EGFR synergistically induces caspase-3-dependent apoptosis in EGFR inhibitor-resistant lung cancer cells via BIM upregulation},
  author={Ji-Young Song and Choung-Soo Kim and Je-Hwan Lee and Se Jin Jang and Sang-Wook Lee and Jung Jin Hwang and Chulsoo Lim and Gilnam Lee and Jeongbeob Seo and Suk Young Cho and Jene Choi},
  journal={Investigational New Drugs},
SummaryEpidermal growth factor receptor (EGFR) gene mutations activate the KRAS-RAF-MEK-ERK pathway in lung cancer cells. EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib induce apoptosis of cancer cells, but prolonged treatment is often associated with acquired resistance. Here, we identified a novel MEK1/2 inhibitor, CZ0775, and compared its cytotoxic effects to those of AZD6244 (selumetinib) in non-small cell lung cancer (NSCLC) cell lines harboring EGFR mutations. The lapatinib… 

Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis

It is demonstrated for the first time that ketoconazole treatment inhibits upregulation of mitochondrial cholesterol and thereby overcomes EGFR‐TKI resistance in lung cancer cells, and is shown to shrink the growth of tumors in an in vivo mouse model of EGFR TKI resistance.

Paxillin confers resistance to tyrosine kinase inhibitors in EGFR-mutant lung cancers via modulating BIM and Mcl-1 protein stability

Evidence is provided indicating that paxillin (PXN) overexpression may confer TKI resistance in EGFR-mutant lung cancer cells, and combining TKI with ERK inhibitors may clinically benefit EGFR -mutant non-small cell lung cancer patients whose tumors exhibit high PXN expression.

Treatment with cucurbitacin B alone and in combination with gefitinib induces cell cycle inhibition and apoptosis via EGFR and JAK/STAT pathway in human colorectal cancer cell lines

Investigation of the apoptotic and antiproliferative effects of CuB as a single agent and in combination with Gef on both HT-29 and HCT-116 cell lines showed that, compared to CuB alone, CuB plus Gef treatment caused a significant growth and cell cycle inhibition and induced apoptosis in both cell lines.

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

Gefitinib treatment markedly inhibited H 1650 cell viability, induced apoptosis and reduced TRAIL expression levels, and induced NSCLC H1650 cell apoptosis by downregulating TRAil expression levels.

Erlotinib and Trametinib in Patients With EGFR-Mutant Lung Adenocarcinoma and Acquired Resistance to a Prior Tyrosine Kinase Inhibitor

Addition of trametinib to erlotinib in the acquired resistance setting in an unselected population is not efficacious, and future studies should focus on targeted therapies in molecularly selected populations.

The apoptotic effect of simvastatin via the upregulation of BIM in nonsmall cell lung cancer cells

The hypothesis that simvastatin has pro-apoptotic effects in epidermal growth factor receptor (EGFR)-mutated lung cancer cell lines via the upregulation of the expression of the BIM protein is investigated and the potential utility of simVastatin as a BIM-targeted treatment for NSCLC is suggested.

MiR-25 reduces PC-9 / BB 4 cell apoptosis sensitivity induced by gefitinib through downregulating BIM

MiR-25 suppressed PC-9/BB4 cell apoptosis induced by gefitinib through targeting BIM, which may play a role in PC- 9/ BB4 cell drug resistance.

miR-16 regulates proliferation and invasion of lung cancer cells via the ERK/MAPK signaling pathway by targeted inhibition of MAPK kinase 1 (MEK1)

Objective The ERK/MAPK signaling pathway regulates cell proliferation and invasion. MAPK kinase 1 (MEK1) is a protein kinase upstream of ERK that can activate the pathway. Expression of microRNA

Targeting Discoidin Domain Receptor 1 (DDR1) Signaling and Its Crosstalk with β1-Integrin Emerges as a Key Factor for Breast Cancer Chemosensitization upon Collagen Type 1 Binding

Findings provide evidence for the highly dynamic adaptation of breast cancer cells in maintaining matrix binding to circumvent cytotoxicity and highlight DDR1 signaling as a target for sensitization approaches.

EGFR TKI resistance in lung cancer cells using RNA sequencing and analytical bioinformatics tools.

Several key proteins, including D USP1, DUSP6, GAB2, and FOS, that could be targeted using novel combination therapies to overcome EGFR TKI resistance in lung cancer are revealed.



Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells

This study provides molecular insights to explain resistance to an MEK inhibitor in human cancer cell lines and revealed that the activation of cAMP-dependent protein kinase A (PKA) was associated with MeK inhibitor resistance.

Gefitinib-resistance is related to BIM expression in non-small cell lung cancer cell lines.

In Gefitinib-sensitive cell lines, Gefitsinib could induce tumor cell apoptosis via upregulation of a proapoptotic protein BIM and small interfering RNA results showed that silencing of BIM could alleviate apoptosis induced by Gefithinib.

Treatment of B-RAF mutant human tumor cells with a MEK inhibitor requires Bim and is enhanced by a BH3 mimetic.

The therapeutic efficacy of MEK inhibition requires concurrent unleashing of apoptosis by a BH3 mimetic and represents a potent combination treatment for tumors harboring B-RAF mutations.

KRAS mutant lung cancer cells are differentially responsive to MEK inhibitor due to AKT or STAT3 activation: Implication for combinatorial approach

Molecular insights are provided that help explain the heterogeneous response to MEK inhibition in KRAS mutant lung cancers, and a rationale for the clinical investigation of combination of MEK and EGFR inhibitor or MeK and JAK2 inhibitor depending on PTEN status is presented.

MEK1/2 inhibitors AS703026 and AZD6244 may be potential therapies for KRAS mutated colorectal cancer that is resistant to EGFR monoclonal antibody therapy.

The ability of two MEK inhibitors currently in clinical trials, AS703026 and AZD6244, to address the challenge posed by the resistance of K-ras mutated colorectal cancers to EGFR mAb is investigated.

Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling.

Modelling acquired resistance to the MEK1/2 inhibitor selumetinib provides important new insights into how tumour cells adapt to new therapeutics and highlights the importance of homoeostatic control mechanisms in the Raf/MEK 1/2/ERK1/) signalling cascade.

Growth-inhibitory and antiangiogenic activity of the MEK inhibitor PD0325901 in malignant melanoma with or without BRAF mutations.

Investigation of the growth-inhibitory and antiangiogenic properties of PD0325901, a novel MEK inhibitor, in human melanoma cells revealed profound modulation of several genes involved in the negative control of MAPK signaling and melanoma cell differentiation, suggesting alternative, potentially relevant mechanisms of action.

KRAS/BRAF mutation status and ERK1/2 activation as biomarkers for MEK1/2 inhibitor therapy in colorectal cancer

Although MEK inhibitors show promise in colorectal cancer, KRAS/BRAF mutation status, but not ERK activation as previously thought, may be useful biomarkers for MEK inhibitor sensitivity.

Differential Sensitivity of ERBB2 Kinase Domain Mutations towards Lapatinib

Interestingly, lapatinib resistance mutations in wt-ERBB2 cells incubated with lapatinIB for prolonged periods of time indicates that these resistance mutations may also cause secondary resistance in Lapatinib-treated patients.

Tumour cell survival signalling by the ERK1/2 pathway

Understanding of how the ERK1/2 pathway regulates BCL-2 proteins to promote survival is reviewed, how this is de-regulated in tumour cells and the opportunities this might afford with the use of new targeted therapies are reviewed.