ArticleInvestigational new drugs2015
BYL719, a selective inhibitor of phosphoinositide 3-Kinase α, enhances the effect of selumetinib (AZD6244, ARRY-142886) in KRAS-mutant non-small cell lung cancer.
Article in Investigational new drugs, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 26 citations in OpenAlex.
- RAS signaling and immune cells: a sinister crosstalk in the tumor microenvironment.Journal of translational medicine · 2023Review
- An Increase in Mucin2 Expression Is Required for Colon Cancer Progression Mediated by L1.International journal of molecular sciences · 2023Article
- BYL719 reverses gefitinib-resistance induced by PI3K/AKT activation in non-small cell lung cancer cells.BMC cancer · 2023Article
- Targeting the PI3K/AKT/mTOR and RAF/MEK/ERK pathways for cancer therapy.Molecular biomedicine · 2022Review
- Clinical Relevance of PD-L1 Expression and CD8+ T Cells' Infiltration in Patients With Lung Invasive Mucinous Adenocarcinoma.Frontiers in oncology · 2021Article
- Invasive mucinous adenocarcinoma of the lung.Translational cancer research · 2019Review
- The antipsychotic agent flupentixol is a new PI3K inhibitor and potential anticancer drug for lung cancer.International journal of biological sciences · 2019Article
- Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy.Nature genetics · 2018Article
- Enhanced anti-tumour activity of the combination of the novel MEK inhibitor WX-554 and the novel PI3K inhibitor WX-037.Cancer chemotherapy and pharmacology · 2016Article
- Enhancement of hyperthermia-induced apoptosis by 5Z-7-oxozeaenol, a TAK1 inhibitor, in A549 cells.Cell stress & chaperones · 2016Article
- Targeting the MEK signaling pathway in non-small cell lung cancer (NSCLC) patients with RAS aberrations.Therapeutic advances in respiratory disease · 2016Review
- Targeting KRAS-mutant non-small cell lung cancer: challenges and opportunities.Acta biochimica et biophysica Sinica · 2016Review
- The comparison between dual inhibition of mTOR with MAPK and PI3K signaling pathways in KRAS mutant NSCLC cell lines.Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine · 2015Article
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Authors and funding
7 authors at 3 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
purposeKRAS is frequently mutated in non-small cell lung cancers (NSCLC), resulting in activation of the MEK/ERK pathway. Because there are currently no drugs that target oncogenic KRAS, MEK inhibitors have been tested clinically as a possible treatment option for patients with NSCLC. However, KRAS-mutant cancers exhibit resistance to MEK inhibitors. Therefore, a combinational strategy is necessary for effective therapy. To address this, we investigated the therapeutic effects of combining selumetinib, a MEK1/2 inhibitor, with BYL719, a PI3Kα inhibitor.
methodsWe evaluated the effects of selumetinib and BYL719 in vitro and in vivo in NSCLC cell lines.
resultsThe combination of BYL719 and selumetinib resulted in synergistic cytotoxic activity compared with the single agents alone in KRAS-mutant NSCLC cells. At the molecular level, we found that AKT activation strongly influenced the sensitivity of KRAS-mutant NSCLC cells to selumetinib. Selumetinib upregulated phospho-AKT and phosphorylated BAD at ser136, which is responsible for intrinsic drug resistance in KRAS-mutant NSCLC cells. In contrast, inhibition of the PI3K/AKT pathway by BYL719 hindered selumetinib-induced BAD phosphorylation and increased the antitumor efficacy of selumetinib. Furthermore, selumetinib and BYL719 combination therapy showed synergy in the suppression of A549 xenograft tumor growth. On analysis of the pharmacodynamics, selumetinib and BYL719 together resulted in effective inhibition of both p-ERK and p-AKT expression in tumor tissue.
conclusionTaken together, these data suggest that combination treatment with selumetinib and BYL719 is a promising therapeutic approach to overcoming resistance to MEK inhibitors.
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