{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:28:00Z","timestamp":1787725680540,"version":"build-2784847793"},"reference-count":61,"publisher":"American Society for Clinical Investigation","issue":"15","license":[{"start":{"date-parts":[[2020,8,6]],"date-time":"2020-08-06T00:00:00Z","timestamp":1596672000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Susan G. Komen","award":["Career Catalyst Grant CCR14299052"],"award-info":[{"award-number":["Career Catalyst Grant CCR14299052"]}]},{"name":"U.S. Department of Defense","award":["Era of Hope Scholar Award BC170037"],"award-info":[{"award-number":["Era of Hope Scholar Award BC170037"]}]},{"name":"NIH\/NCI","award":["2P50CA098131"],"award-info":[{"award-number":["2P50CA098131"]}]},{"name":"NIH\/NCI","award":["R00CA181491"],"award-info":[{"award-number":["R00CA181491"]}]},{"DOI":"10.13039\/100007208","name":"Vanderbilt Ingram Cancer Center","doi-asserted-by":"crossref","award":["Support Grant P30 CA68485"],"award-info":[{"award-number":["Support Grant P30 CA68485"]}],"id":[{"id":"10.13039\/100007208","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,6]]},"abstract":"<jats:p>\n                    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\u2013stromal crosstalk in establishing chemoresistance are complex and largely unclear. Here we report molecular studies of paired TNBC patient\u2013derived xenografts (PDXs) established before and after the development of chemoresistance. Interestingly, the chemoresistant model acquired a distinct\n                    <jats:italic>\n                      KRAS\n                      <jats:sup>Q61R<\/jats:sup>\n                    <\/jats:italic>\n                    mutation that activates K-Ras. The chemoresistant\n                    <jats:italic>KRAS<\/jats:italic>\n                    -mutant model showed gene expression and proteomic changes indicative of altered tumor cell metabolism. Specifically,\n                    <jats:italic>KRAS<\/jats:italic>\n                    -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\n                    <jats:italic>KRAS-<\/jats:italic>\n                    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\u2013recruiting 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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.134290","type":"journal-article","created":{"date-parts":[[2020,7,7]],"date-time":"2020-07-07T12:11:49Z","timestamp":1594123909000},"source":"Crossref","is-referenced-by-count":39,"title":["MEK activation modulates glycolysis and supports suppressive myeloid cells in TNBC"],"prefix":"10.1172","volume":"5","author":[{"given":"Derek A.","family":"Franklin","sequence":"first","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe T.","family":"Sharick","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering, Vanderbilt University, Nashville, Tennessee, USA."},{"name":"Morgridge Institute for Research, University of Wisconsin\u2013Madison, Wisconsin, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula I.","family":"Ericsson-Gonzalez","sequence":"additional","affiliation":[{"name":"Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violeta","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillip T.","family":"Dean","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan R.","family":"Opalenik","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4725-5970","authenticated-orcid":true,"given":"Stefano","family":"Cairo","sequence":"additional","affiliation":[{"name":"Xentech, Genopole Campus 3, Evry, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Gabriel","family":"Judde","sequence":"additional","affiliation":[{"name":"Xentech, Genopole Campus 3, Evry, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael T.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Baylor College of Medicine, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny C.","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7227-1764","authenticated-orcid":true,"given":"Melinda E.","family":"Sanders","sequence":"additional","affiliation":[{"name":"Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA."},{"name":"Department of Pathology, Microbiology and Immunology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca S.","family":"Cook","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6320-7637","authenticated-orcid":true,"given":"Melissa C.","family":"Skala","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, University of Wisconsin\u2013Madison, Wisconsin, USA."},{"name":"Department of Biomedical Engineering, College of Engineering, University of Wisconsin\u2013Madison, Wisconsin, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4567-3239","authenticated-orcid":true,"given":"Jennifer","family":"Bordeaux","sequence":"additional","affiliation":[{"name":"Navigate BioPharma Services, Inc., Carlsbad, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7009-205X","authenticated-orcid":true,"given":"Jehovana","family":"Orozco Bender","sequence":"additional","affiliation":[{"name":"Navigate BioPharma Services, Inc., Carlsbad, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Vaupel","sequence":"additional","affiliation":[{"name":"Navigate BioPharma Services, Inc., Carlsbad, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Geiss","sequence":"additional","affiliation":[{"name":"NanoString Technologies, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Hinerfeld","sequence":"additional","affiliation":[{"name":"NanoString Technologies, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4263-5974","authenticated-orcid":true,"given":"Justin M.","family":"Balko","sequence":"additional","affiliation":[{"name":"Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA."},{"name":"Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2020,8,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI45014"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-1081"},{"issue":"8","key":"B3","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.bbamcr.2006.10.001","article-title":"Roles of the Raf\/MEK\/ERK pathway in cell growth, malignant transformation and drug resistance","volume":"1773","author":"McCubrey","year":"2007","journal-title":"Biochim Biophys Acta"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.66"},{"key":"B5","doi-asserted-by":"crossref","DOI":"10.1186\/1471-2407-10-136","article-title":"Lack of evidence for KRAS oncogenic mutations in triple-negative breast cancer","volume":"10","author":"S\u00e1nchez-Mu\u00f1oz","year":"2010","journal-title":"BMC Cancer"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2795"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1385"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.08.008"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.10.054"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-15-1125"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.01.024"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.01.058"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-3842"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-2644"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI44362"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-012-2092-7"},{"issue":"6","key":"B17","doi-asserted-by":"crossref","first-page":"677","DOI":"10.4161\/cbt.2.6.535","article-title":"Docetaxel cytotoxicity is enhanced by inhibition of the Raf\/MEK\/ERK signal transduction pathway","volume":"2","author":"Navolanic","year":"2003","journal-title":"Cancer Biol Ther"},{"issue":"suppl 15","key":"B18","article-title":"Cobimetinib (C) + paclitaxel (P) as first-line treatment in patients (pts) with advanced triple-negative breast cancer (TNBC): Updated results and biomarker data from the phase 2 COLET study","volume":"34","author":"Brufsky","year":"2016","journal-title":"J Clin Oncol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-12-0511"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3082"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0286"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-12-4081"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aam7550"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14880"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912226107"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.03.022"},{"key":"B27","doi-asserted-by":"crossref","DOI":"10.1038\/ncomms15617","article-title":"Codon bias imposes a targetable limitation on KRAS-driven therapeutic resistance","volume":"8","author":"Ali","year":"2017","journal-title":"Nat Commun"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-0527"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1364\/BOE.3.000075"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-bioeng-071811-150108"},{"issue":"11","key":"B31","doi-asserted-by":"crossref","first-page":"4764","DOI":"10.1016\/S0021-9258(17)30079-0","article-title":"Oxidation-reduction ratio studies of mitochondria in freeze-trapped samples. NADH and flavoprotein fluorescence signals","volume":"254","author":"Chance","year":"1979","journal-title":"J Biol Chem"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0900780106"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206360109"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.14118"},{"key":"B35","doi-asserted-by":"crossref","DOI":"10.1038\/cddis.2014.297","article-title":"Autophagy promotes paclitaxel resistance of cervical cancer cells: involvement of Warburg effect activated hypoxia-induced factor 1-\u03b1-mediated signaling","volume":"5","author":"Peng","year":"2014","journal-title":"Cell Death Dis"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.08.006"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-2976"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3955"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.04.022"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-3873"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nature14492"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.3.1101"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0900780106"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nature11412"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0095"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-1308"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00728-9"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1172\/JCI86477"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03051-z"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2019.02.008"},{"issue":"suppl 4","key":"B51","article-title":"Abstract OT2-01-02: COLET: a multistage, phase 2 study evaluating the safety and efficacy of a doublet regimen of cobimetinib (C) in combination with paclitaxel (P) or triplet regimens of C in combination with atezolizumab (atezo) plus either P or nab-paclitaxel (nab-P) in metastatic triple-negative breast cancer (TNBC)","volume":"77","author":"Miles","year":"2017","journal-title":"J Clin Oncol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.01.004"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-0078"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-2200"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.4161\/cbt.8.6.7690"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(12)70270-X"},{"issue":"21","key":"B57","doi-asserted-by":"crossref","first-page":"5250","DOI":"10.1158\/1078-0432.CCR-18-0309","article-title":"Quantitative spatial profiling of PD-1\/PD-L1 interaction and HLA-DR\/IDO-1 predicts improved outcomes of anti-PD-1 therapies in metastatic melanoma","volume":"24","author":"Johnson","year":"2018","journal-title":"Clin Cancer Res"},{"key":"B58","doi-asserted-by":"crossref","unstructured":"Walsh AJ, Skala MC. An automated image processing routine for segmentation of cell cytoplasms in high-resolution autofluorescence images. SPIE Digital Library. https:\/\/doi.org\/10.1117\/12.2040644 Published February 28, 2014. Accessed July 10, 2020","DOI":"10.1117\/12.2040644"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/nature10983"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/nature11003"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2007-8-5-r76"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/134290\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T12:11:08Z","timestamp":1779192668000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/134290"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,6]]},"references-count":61,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2020,8,6]]},"published-print":{"date-parts":[[2020,8,6]]}},"alternative-id":["10.1172\/jci.insight.134290"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.134290","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,6]]},"article-number":"e134290"}}