The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors
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Abstract
Purpose: Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking. Experimental Design: We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1–targeted immunotherapy in mouse models of breast cancer. Results: Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras–MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer. Conclusions: These data suggest the possibility that Ras–MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1–targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. Clin Cancer Res; 22(6); 1499–509. ©2015 AACR.
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“RAS-targeted therapy abrogated RAS-MAPK/PI3K-AKT-involved immune evasion, synergizing with α-PD-1/PD-L1 [213, 214].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [214]
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“trametinib promotes PD-L1 upregulation in mouse breast cancer cells, in vitro and in vivo (Loi et al., 2016)”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Loi et al., 2016
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Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0095 · Cited by 17,455
Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay‐Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,320
Nishimura, R., Osako, T., Nishiyama, Y., Tashima, R., Nakano, M., Fujisue, M., Toyozumi, Y., & Arima, N. (2013) · Oncology · doi:10.1159/000353099 · Cited by 13,239
Safety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628
Comprehensive molecular portraits of human breast tumours
The Cancer Genome Atlas Network (2012) · Nature · doi:10.1038/nature11412 · Cited by 12,129
PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
Le, D. T., Uram, J. N., Wang, H., Bartlett, B. R., Kemberling, H., Eyring, A. D., Skora, A. D., Luber, B. S., Azad, N. S., Laheru, D., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1500596 · Cited by 9,377
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504030 · Cited by 8,157
Safety and activity of anti-PD-L1 antibody in patients with advanced cancer
Brahmer, J. R., Tykodi, S. S., Chow, L. Q. M., Hwu, W.-J., Topalian, S. L., Hwu, P., Drake, C. G., Camacho, L. H., Kauh, J., Odunsi, K., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200694 · Cited by 7,945
Research works printed but not linked: 1
- Emens, 2015, Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC)
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Bianchini, G., Balko, J. M., Mayer, I. A., Sanders, M. E., & Gianni, L. (2016) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.66 · Cited by 3,079
Self-citationGarrido-Castro, A. C., Lin, N. U., & Polyak, K. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1177 · Cited by 1,451
Combination strategies with PD-1/PD-L1 blockade: current advances and future directions
Yi, M., Zheng, X., Niu, M., Zhu, S., Ge, H., & Wu, K. (2022) · Molecular Cancer · doi:10.1186/s12943-021-01489-2 · Cited by 1,445
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Yi, M., Niu, M., Xu, L., Luo, S., & Wu, K. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-01027-5 · Cited by 681
Eng, C., Kim, T. W., Bendell, J., Argilés, G., Tebbutt, N. C., Di Bartolomeo, M., Falcone, A., Fakih, M., Kozloff, M., Segal, N. H., et al. (2019) · The Lancet Oncology · doi:10.1016/s1470-2045(19)30027-0 · Cited by 577
Therapeutic strategies to target RAS-mutant cancers
Ryan, M. B., & Corcoran, R. B. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0105-0 · Cited by 420
New insights into the role of EMT in tumor immune escape
Terry, S., Savagner, P., Ortiz‐Cuaran, S., Mahjoubi, L., Saintigny, P., Thiery, J., & Chouaib, S. (2017) · Molecular Oncology · doi:10.1002/1878-0261.12093 · Cited by 414
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Communication between EMT and PD-L1 signaling: New insights into tumor immune evasion
Jiang, Y., & Zhan, H. (2020) · Cancer Letters · doi:10.1016/j.canlet.2019.10.013 · Cited by 319
Luo, N., Nixon, M. J., Gonzalez-Ericsson, P. I., Sanchez, V., Opalenik, S. R., Li, H., Zahnow, C. A., Nickels, M. L., Liu, F., Tantawy, M. N., et al. (2018) · Nature Communications · doi:10.1038/s41467-017-02630-w · Cited by 275
Self-citationImmunomodulation by targeted anticancer agents
Petroni, G., Buqué, A., Zitvogel, L., Kroemer, G., & Galluzzi, L. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.11.009 · Cited by 212
Targeting RAS–RAF–MEK–ERK signaling pathway in human cancer: Current status in clinical trials
Song, Y., Bi, Z., Liu, Y., Qin, F., Wei, Y., & Wei, X. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2022.05.006 · Cited by 212
Briere, D. M., Li, S., Calinisan, A., Sudhakar, N., Aranda, R., Hargis, L., Peng, D. H., Deng, J., Engstrom, L. D., Hallin, J., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-20-0462 · Cited by 168
Zhai, J., Gu, X., Liu, Y., Hu, Y., Jiang, Y., & Zhang, Z. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1152934 · Cited by 131
Dushyanthen, S., Teo, Z. L., Caramia, F., Savas, P., Mintoff, C. P., Virassamy, B., Henderson, M. A., Luen, S. J., Mansour, M., Kershaw, M. H., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00728-9 · Cited by 124
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Wang, Y., Sun, Q., Mu, N., Sun, X., Wang, Y., Fan, S., Su, L., & Liu, X. (2020) · Cell Communication and Signaling · doi:10.1186/s12964-020-00612-y · Cited by 124
Effect of CCL5 expression in the recruitment of immune cells in triple negative breast cancer
Araujo, J. M., Gomez, A. C., Aguilar, A., Salgado, R., Balko, J. M., Bravo, L., Doimi, F., Bretel, D., Morante, Z., Flores, C., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-23099-7 · Cited by 108
Self-citationGogas, H., Dréno, B., Larkin, J., Demidov, L., Stroyakovskiy, D., Eroglu, Z., Francesco Ferrucci, P., Pigozzo, J., Rutkowski, P., Mackiewicz, J., et al. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2020.12.004 · Cited by 102
Soundararajan, R., Fradette, J., Konen, J., Moulder, S., Zhang, X., Gibbons, D., Varadarajan, N., Wistuba, I., Tripathy, D., Bernatchez, C., et al. (2019) · Cancers · doi:10.3390/cancers11050714 · Cited by 103
Brufsky, A., Kim, S. B., Zvirbule, Ž., Eniu, A., Mebis, J., Sohn, J. H., Wongchenko, M., Chohan, S., Amin, R., Yan, Y., et al. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.01.065 · Cited by 92
Self-citationBaumann, D., Hägele, T., Mochayedi, J., Drebant, J., Vent, C., Blobner, S., Noll, J. H., Nickel, I., Schumacher, C., Boos, S. L., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15979-2 · Cited by 76
Kang, S.-H., Keam, B., Ahn, Y.-O., Park, H.-R., Kim, M., Kim, T. M., Kim, D.-W., & Heo, D. S. (2019) · OncoImmunology · doi:10.1080/2162402x.2018.1515057 · Cited by 72
Peng, D. H., Rodriguez, B. L., Diao, L., Gaudreau, P.-O., Padhye, A., Konen, J. M., Ochieng, J. K., Class, C. A., Fradette, J. J., Gibson, L., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22875-w · Cited by 72
Gandini, A., Puglisi, S., Pirrone, C., Martelli, V., Catalano, F., Nardin, S., Seeber, A., Puccini, A., & Sciallero, S. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1161048 · Cited by 42
Refining patient selection for breast cancer immunotherapy: beyond PD-L1
Kossai, M., Radosevic-Robin, N., & Penault-Llorca, F. (2021) · ESMO Open · doi:10.1016/j.esmoop.2021.100257 · Cited by 36
Metadata
- Authors
- Loi, S., Dushyanthen, S., Beavis, P. A., Salgado, R., Denkert, C., Savas, P., Combs, S., Rimm, D. L., Giltnane, J. M., Estrada, M. V., Sánchez, V., Sanders, M. E., Cook, R. S., Pilkinton, M. A., Mallal, S. A., Wang, K., Miller, V. A., Stephens, P. J., Yelensky, R., Doimi, F. D., Gómez, H., Ryzhov, S. V., Darcy, P. K., Arteaga, C. L., & Balko, J. M.
- Affiliations
- The University of Melbourne (AU)
- Peter MacCallum Cancer Centre (AU)
- Institut Jules Bordet (BE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Yale University (US)
- Vanderbilt University (US)
- 7Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
- Foundation Medicine (United States) (US)
- Instituto Nacional de Enfermedades Neoplásicas (PE)
- Maine Medical Center Research Institute (US)
- Corresponding author
- Loi, Sherene
- Balko, Justin M.
- ORCID
- Loi, Sherene
- Dushyanthen, Sathana
- Beavis, Paul A.
- Salgado, Roberto
- Denkert, Carsten
- Savas, Peter
- Rimm, David L.
- Giltnane, Jennifer M.
- Estrada, Monica V.
- Sanders, Melinda E.
- Cook, Rebecca S.
- Pilkinton, Mark A.
- Mallal, Simon A.
- Miller, Vincent A.
- Stephens, Phil J.
- Yelensky, Roman
- Doimi, Franco D.
- Gómez, Henry
- Ryzhov, Sergey V.
- Darcy, Phillip K.
- Arteaga, Carlos L.
- Balko, Justin M.
- Venue
- Clinical Cancer Research
- Published
- 2016-03-14
- Volume
- 22
- Issue
- 6
- Pages
- 1499-1509
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4794351
- OpenAlex
- W1933761723
- Cited by
- 536
- References
- 41
- Citations by year
- 2026: 14 · 2025: 32 · 2024: 29 · 2023: 67 · 2022: 62 · 2021: 94 · 2020: 68 · 2019: 60 · 2018: 51 · 2017: 44 · 2016: 14
- FWCI
- 15.90
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-02-15)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Murdoch University Research Portal (submittedVersion)
- Funders
- National Institutes of Health (1k99ca181491-01a1)
- National Cancer Institute (1K99CA181491, K99 CA181491, P50CA098131, R00CA181491, P30CA068485)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- triple-negative breast cancer, tumor-infiltrating lymphocytes, RAS/MAPK pathway, MEK inhibitors, PD-1/PD-L1 inhibitors, MHC class I expression, immune evasion, combination immunotherapy, predictive biomarkers, antitumor immunity
- MeSH terms
- Animals, Disease Models, Animal, Female, Humans, Mortality, Phenotype, Signal Transduction, Biomarkers, Immunophenotyping, Lymphocytes, Tumor-Infiltrating, Disease Progression, ras Proteins, Gene Expression Profiling, Mitogen-Activated Protein Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Immunomodulation, Transcriptome, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Triple Negative Breast Neoplasms
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