ArticleCancers2019
Overactivation of Akt Contributes to MEK Inhibitor Primary and Acquired Resistance in Colorectal Cancer Cells.
Article in Cancers, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- Therapeutic Targets for Overcoming BCR::ABL1 Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia.Oncology research · 2026Review
- The challenges and progress of CAR-T cell therapy in the treatment of solid tumors.Molecular and cellular biochemistry · 2025Review
- Targeted Therapy for Complex Lymphatic Anomalies in Patients with Noonan Syndrome and Related Disorders.International journal of molecular sciences · 2025Article
- Oxaliplatin and 5-fluorouracil promote epithelial-mesenchymal transition via activation of KRAS/ERK/NF-κB pathway in KRAS-mutated colon cancer cells.Molecular and cellular biochemistry · 2025Article
- MDM2 inhibitors induce apoptosis by suppressing MDM2 and enhancing p53, Bax, Puma and Noxa expression levels in imatinib‑resistant chronic myeloid leukemia cells.Biomedical reports · 2025Article
- Targeting Non-V600 Mutations in BRAF: A Single Institution Retrospective Analysis and Review of the Literature.Drugs in R&D · 2024Review
- Preclinical evidence for employing MEK inhibition in NRAS mutated pediatric gastroenteropancreatic neuroendocrine-like tumors.Translational oncology · 2024Article
- RGD-p21Ras-scFv expressed prokaryotically on a pilot scale inhibits ras-driven colorectal cancer growth by blocking p21Ras-GTP.BMC cancer · 2024Article
- Lasting response by vertical inhibition with cetuximab and trametinib in KRAS-mutated colorectal cancer patient-derived xenografts.Molecular oncology · 2023Article
- Article
- Bim downregulation by activation of NF-κB p65, Akt, and ERK1/2 is associated with adriamycin and dexamethasone resistance in multiple myeloma cells.Clinical and experimental medicine · 2023Article
- Establishment and characterization of patient-derived xenograft of a rare pediatric anaplastic pleomorphic xanthoastrocytoma (PXA) bearing a CDC42SE2-BRAF fusion.Scientific reports · 2023Article
- Activation of ERK1/2 by MOS and TPL2 leads to dasatinib resistance in chronic myeloid leukaemia cells.Cell proliferation · 2023Article
- A targeted genetic modifier screen in Drosophila uncovers vulnerabilities in a genetically complex model of colon cancer.G3 (Bethesda, Md.) · 2023Article
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- Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function.Frontiers in cell and developmental biology · 2023Article
- Article
- Dimethyl Fumarate Induces Apoptosis via Inhibition of NF-κB and Enhances the Effect of Paclitaxel and Adriamycin in Human TNBC Cells.International journal of molecular sciences · 2022Article
- PI3K/Akt/YAP signaling promotes migration and invasion of DLD-1 colorectal cancer cells.Oncology letters · 2022Article
- Concurrent inhibition of FAK/SRC and MEK overcomes MEK inhibitor resistance in Neurofibromatosis Type I related malignant peripheral nerve sheath tumors.Frontiers in oncology · 2022Article
Corrections and comments
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
RAS and BRAF-mutated colorectal cancers are associated with resistance to chemotherapy and poor prognosis, highlighting the need for new therapeutic strategies. Although these cancers sometimes respond to mitogen activated protein kinase kinase (MEK) inhibitor treatment, they often acquire resistance via mechanisms, which are poorly understood. Here, we investigated the mechanism of MEK inhibitor resistance in primary- and acquired-resistant cells. Cell viability was examined using the trypan blue dye exclusion assay. Protein expression was analyzed by western blotting. Somatic mutations in colorectal cancer cells were investigated using the polymerase chain reaction array. PD0325901 and trametinib induced cell death in LoVo and Colo-205 cells but not in DLD-1 and HT-29 cells, which have a PIK3CA mutation constitutively activating Akt and NF-κB. Treatment with PD0325901 and trametinib suppressed ERK1/2 activation in all four cell lines but only induced Akt and NF-κB activation in DLD-1 and HT-29 cells. Inhibition of Akt but not NF-κB, overcame MEK inhibitor resistance in DLD-1 and HT-29 cells. Acquired-resistant LoVo/PR, Colo-205/PR and LoVo/TR cells have constitutively active Akt due to a M1043V mutation in the kinase activation loop of PIK3CA and Akt inhibitor resensitized these cells to MEK inhibitor. These results demonstrate that the overactivation of Akt plays a critical role in MEK inhibitor primary and acquired resistance and implicate combined Akt/MEK inhibition as a potentially useful treatment for RAS/BRAF-mutated colorectal cancer.
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