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MEK activation modulates glycolysis and supports suppressive myeloid cells in TNBC.
Franklin, Derek A; Sharick, Joe T; Ericsson-Gonzalez, Paula I; Sanchez, Violeta; Dean, Phillip T; Opalenik, Susan R; Cairo, Stefano; Judde, Jean-Gabriel; Lewis, Michael T; Chang, Jenny C; Sanders, Melinda E; Cook, Rebecca S; Skala, Melissa C; Bordeaux, Jennifer; Orozco Bender, Jehovana; Vaupel, Christine; Geiss, Gary; Hinerfeld, Douglas; Balko, Justin M.
Afiliação
  • Franklin DA; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Sharick JT; Department of Biomedical Engineering, School of Engineering, Vanderbilt University, Nashville, Tennessee, USA.
  • Ericsson-Gonzalez PI; Morgridge Institute for Research, University of Wisconsin-Madison, Wisconsin, USA.
  • Sanchez V; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
  • Dean PT; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
  • Opalenik SR; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Cairo S; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
  • Judde JG; Xentech, Genopole Campus 3, Evry, France.
  • Lewis MT; Xentech, Genopole Campus 3, Evry, France.
  • Chang JC; Baylor College of Medicine, Houston, Texas, USA.
  • Sanders ME; Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas, USA.
  • Cook RS; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
  • Skala MC; Department of Pathology, Microbiology and Immunology and.
  • Bordeaux J; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville Tennessee, USA.
  • Orozco Bender J; Morgridge Institute for Research, University of Wisconsin-Madison, Wisconsin, USA.
  • Vaupel C; Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Wisconsin, USA.
  • Geiss G; Navigate BioPharma Services, Inc., Carlsbad, California, USA.
  • Hinerfeld D; Navigate BioPharma Services, Inc., Carlsbad, California, USA.
  • Balko JM; Navigate BioPharma Services, Inc., Carlsbad, California, USA.
JCI Insight ; 5(15)2020 08 06.
Article em En | MEDLINE | ID: mdl-32634121
Triple-negative breast cancers (TNBCs) are heterogeneous and aggressive, with high mortality rates. TNBCs frequently respond to chemotherapy, yet many patients develop chemoresistance. The molecular basis and roles for tumor cell-stromal crosstalk in establishing chemoresistance are complex and largely unclear. Here we report molecular studies of paired TNBC patient-derived xenografts (PDXs) established before and after the development of chemoresistance. Interestingly, the chemoresistant model acquired a distinct KRASQ61R mutation that activates K-Ras. The chemoresistant KRAS-mutant model showed gene expression and proteomic changes indicative of altered tumor cell metabolism. Specifically, KRAS-mutant PDXs exhibited increased redox ratios and decreased activation of AMPK, a protein involved in responding to metabolic homeostasis. Additionally, the chemoresistant model exhibited increased immunosuppression, including expression of CXCL1 and CXCL2, cytokines responsible for recruiting immunosuppressive leukocytes to tumors. Notably, chemoresistant KRAS-mutant tumors harbored increased numbers of granulocytic myeloid-derived suppressor cells (gMDSCs). Interestingly, previously established Ras/MAPK-associated gene expression signatures correlated with myeloid/neutrophil-recruiting CXCL1/2 expression and negatively with T cell-recruiting chemokines (CXCL9/10/11) across patients with TNBC, even in the absence of KRAS mutations. MEK inhibition induced tumor suppression in mice while reversing metabolic and immunosuppressive phenotypes, including chemokine production and gMDSC tumor recruitment in the chemoresistant KRAS-mutant tumors. These results suggest that Ras/MAPK pathway inhibitors may be effective in some breast cancer patients to reverse Ras/MAPK-driven tumor metabolism and immunosuppression, particularly in the setting of chemoresistance.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas ras / MAP Quinase Quinase 1 / Neoplasias de Mama Triplo Negativas / Células Supressoras Mieloides / Glicólise / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas ras / MAP Quinase Quinase 1 / Neoplasias de Mama Triplo Negativas / Células Supressoras Mieloides / Glicólise / Antineoplásicos Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article