ArticleThe Journal of biological chemistry2012
The PP242 mammalian target of rapamycin (mTOR) inhibitor activates extracellular signal-regulated kinase (ERK) in multiple myeloma cells via a target of rapamycin complex 1 (TORC1)/eukaryotic translation initiation factor 4E (eIF-4E)/RAF pathway and activation is a mechanism of resistance.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 77 citations in OpenAlex.
- Targeting mTOR signaling pathways in multiple myeloma: biology and implication for therapy.Cell communication and signaling : CCS · 2024Review
- PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.Molecular cancer · 2023Review
- Exosomes are involved in the intercellular transfer of rapamycin resistance in the breast cancer cells.BioImpacts : BI · 2023Article
- Autophagy and Apoptosis: Current Challenges of Treatment and Drug Resistance in Multiple Myeloma.International journal of molecular sciences · 2022Review
- Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma.Nature communications · 2022Article
- Sensitization of FOLFOX-resistant colorectal cancer cells via the modulation of a novel pathway involving protein phosphatase 2A.iScience · 2022Article
- Therapeutic Aspects and Molecular Targets of Autophagy to Control Pancreatic Cancer Management.Biomedicines · 2022Review
- The effect of dexamethasone on uterine receptivity, mediated by the ERK1/2-mTOR pathway, and the implantation window: An experimental study.International journal of reproductive biomedicine · 2022Article
- Activation of ERK and p38 Reduces AZD8055-Mediated Inhibition of Protein Synthesis in Hepatocellular Carcinoma HepG2 Cell Line.International journal of molecular sciences · 2021Article
- A dual-targeted molecular therapy of PP242 and cetuximab plays an anti-tumor effect through EGFR downstream signaling pathways in colorectal cancer.Journal of gastrointestinal oncology · 2021Article
- Calcitonin administration improves endometrial receptivity via regulation of LIF, Muc-1 and microRNA Let-7a in mice.Journal of cellular physiology · 2019Article
- Article
- Mechanisms shaping the role of ERK1/2 in cellular senescence (Review).Molecular medicine reports · 2019Review
- Translational Control of Canonical and Non-Canonical Translation Initiation Factors at the Sea Urchin Egg to Embryo Transition.International journal of molecular sciences · 2019Article
- Arsenite-induced apoptosis can be attenuatedToxicology research · 2019Article
- NVP-BEZ235-induced autophagy as a potential therapeutic approach for multiple myeloma.American journal of translational research · 2019Article
- HSP70 Acetylation Prevents Combined mTORC1/2 Inhibitor and Curcumin Treatment-Induced Apoptosis.Molecules (Basel, Switzerland) · 2018Article
- mTORC1/2 inhibitor and curcumin induce apoptosis through lysosomal membrane permeabilization-mediated autophagy.Oncogene · 2018Article
- A molecular cascade modulates MAP1B and confers resistance to mTOR inhibition in human glioblastoma.Neuro-oncology · 2018Article
- The WT1/MVP-Mediated Stabilization on mTOR/AKT Axis Enhances the Effects of Cisplatin in Non-small Cell Lung Cancer by a Reformulated Yu Ping Feng San Herbal Preparation.Frontiers in pharmacology · 2018Article
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7 authors at 2 institutions in 1 country.
Funding
Abstract
Activation of PI3-K-AKT and ERK pathways is a complication of mTOR inhibitor therapy. Newer mTOR inhibitors (like pp242) can overcome feedback activation of AKT in multiple myeloma (MM) cells. We, thus, studied if feedback activation of ERK is still a complication of therapy with such drugs in this tumor model. PP242 induced ERK activation in MM cell lines as well as primary cells. Surprisingly, equimolar concentrations of rapamycin were relatively ineffective at ERK activation. Activation was not correlated with P70S6kinase inhibition nor was it prevented by PI3-kinase inhibition. ERK activation was prevented by MEK inhibitors and was associated with concurrent stimulation of RAF kinase activity but not RAS activation. RAF activation correlated with decreased phosphorylation of RAF at Ser-289, Ser-296, and Ser-301 inhibitory residues. Knockdown studies confirmed TORC1 inhibition was the key proximal event that resulted in ERK activation. Furthermore, ectopic expression of eIF-4E blunted pp242-induced ERK phosphorylation. Since pp242 was more potent than rapamycin in causing sequestering of eIF-4E, a TORC1/4E-BP1/eIF-4E-mediated mechanism of ERK activation could explain the greater effectiveness of pp242. Use of MEK inhibitors confirmed ERK activation served as a mechanism of resistance to the lethal effects of pp242. Thus, although active site mTOR inhibitors overcome AKT activation often seen with rapalog therapy, feedback ERK activation is still a problem of resistance, is more severe than that seen with use of first generation rapalogs and is mediated by a TORC1- and eIF-4E-dependent mechanism ultimately signaling to RAF.
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