title: Integrin β1, myosin light chain kinase and myosin IIA are required for activation of PI3K-AKT signaling following MEK inhibition in metastatic triple negative breast cancer.
abstract: The effectiveness of targeted therapies against the Ras-ERK signaling pathway are limited due to adaptive resistance of tumor cells. Inhibition of the Ras-ERK pathway can result in activation of the PI3K-AKT pathway, thereby diminishing the therapeutic effects of targeting ERK signaling. Here we investigated the crosstalk between the Ras-ERK and PI3K-AKT pathways in MDA-MB-231 breast cancer cell lines that have a preference to metastasize to lung (LM2), brain (BrM2) or bone (BoM2). Inhibition of the Ras-ERK pathway reduced motility in both parental and BoM2 cells. In contrast, inhibition of the Ras-ERK pathway in BrM2 and LM2 cells resulted in activation of PI3K-AKT signaling that was responsible for continued cell motility. Analysis of the cross talk between Ras-ERK and PI3K-AKT signaling pathways revealed integrin β1, myosin light chain kinase (MLCK) and myosin IIA are required for the activation of PI3K-AKT following inhibition of the Ras-ERK pathway. Furthermore, feedback activation of the PI3K-AKT pathway following MEK suppression was independent of the epidermal growth factor receptor. Thus, integrin β1, MLCK, and myosin IIA are factors in the development of resistance to MEK inhibitors. These proteins could provide an opportunity to develop markers and therapeutic targets in a subgroup of triple negative breast cancer (TNBC) that exhibit resistance against MEK inhibition.
authors: Department of Biological Sciences, Korean Advanced Institute of Science and Technology Daejeon, Korea.
authors: Cheolwon
authors: C
authors: Choi
authors: Department of Biological Sciences, Korean Advanced Institute of Science and Technology Daejeon, Korea.
authors: Junyeob
authors: J
authors: Kwon
authors: Department of Biological Sciences, Korean Advanced Institute of Science and Technology Daejeon, Korea.
authors: Sunyoung
authors: S
authors: Lim
authors: Department of Biological Sciences, Korean Advanced Institute of Science and Technology Daejeon, Korea.
authors: David M
authors: DM
authors: Helfman
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D009219:Myosin-Light-Chain Kinase / Q000235:genetics / Q000378:metabolism*; D024507:Nonmuscle Myosin Type IIA / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D019012:Integrin beta1; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D009219:Myosin-Light-Chain Kinase; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D024507:Nonmuscle Myosin Type IIA; D018631:ras Proteins
keywords: FAK; MEK resistance; MLCK; integrin β1; myosin IIA