ArticleThoracic cancer2016
MEK inhibitor can reverse the resistance to bevacizumab in A549 cells harboring Kirsten rat sarcoma oncogene homolog mutation.
Article in Thoracic cancer, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed, 9 citations in OpenAlex.
- Small Non-Coding RNAs in Leukemia.Cancers · 2022Review
- Identification of Novel Lung Cancer Driver Genes Connecting Different Omics Levels With a Heat Diffusion Algorithm.Frontiers in cell and developmental biology · 2022Article
- MiR-199a-5p-HIF-1α-STAT3 Positive Feedback Loop Contributes to the Progression of Non-Small Cell Lung Cancer.Frontiers in cell and developmental biology · 2020Article
- Novel Therapeutic Anti-ADAM17 Antibody A9(B8) Enhances EGFR-TKI-Mediated Anticancer Activity in NSCLC.Translational oncology · 2019Article
- Targeting the KRAS Pathway in Non-Small Cell Lung Cancer.The oncologist · 2016Review
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Authors and funding
9 authors at 7 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundBevacizumab (BV) is broadly used to treat a number of cancers; however, BV resistance mechanisms and strategies to overcome this resistance are yet to be determined.
methodsWe established xenograft mice models harboring Kirsten rat sarcoma oncogene homolog (KRAS) mutations based on the A549 cell line, and tested the responses of xenograft tumors to a series of drugs in ex vivo and in vivo experiments. Changes in transcriptive level were analyzed by ribonucleic acid (RNA) sequencing and the expressions of connexins were determined by immunohistochemistry staining.
resultsA549 cell mutation type (KRAS G12S) was confirmed by sequencing. After treating the xenograft tumors with BV, the median interval time from BV administration to tumor volume more than 2.5-fold of the original was 37 days, compared with 21 days in the control (P = 0.025). A549 cells showed resistantance to selumitinib (MEK inhibitor) but were sensitive to selumitinib plus BEZ235 (phosphoinositide 3-kinase/mammalian target of rapamycin dual inhibitor). However, selumitinib could effectively reverse the resistance to BV in in vivo experiments. RNA sequencing showed that mouse genes, but not human genes, activated the mitogen-activated protein kinase signaling pathway, accompanied by activation of the Wnt and Hedgehog pathways. Connexin43 (S261) was phosphorylated before and during BV treatment, and subsequently transitioned to negative phosphorylated-connexin 43-S261 after resistance to BV.
conclusionCombining an MEK inhibitor with BV was a potential strategy to reverse initial BV resistance. Phosphorylated-connexin 43 might be associated with the response to BV.
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