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KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer.
Liao, Wenting; Overman, Michael J; Boutin, Adam T; Shang, Xiaoying; Zhao, Di; Dey, Prasenjit; Li, Jiexi; Wang, Guocan; Lan, Zhengdao; Li, Jun; Tang, Ming; Jiang, Shan; Ma, Xingdi; Chen, Peiwen; Katkhuda, Riham; Korphaisarn, Krittiya; Chakravarti, Deepavali; Chang, Andrew; Spring, Denise J; Chang, Qing; Zhang, Jianhua; Maru, Dipen M; Maeda, Dean Y; Zebala, John A; Kopetz, Scott; Wang, Y Alan; DePinho, Ronald A.
Afiliação
  • Liao W; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou
  • Overman MJ; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Boutin AT; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Shang X; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Zhao D; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Dey P; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Li J; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Wang G; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Lan Z; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Li J; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Tang M; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Jiang S; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Ma X; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chen P; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Katkhuda R; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Korphaisarn K; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chakravarti D; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chang A; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Spring DJ; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Chang Q; Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Zhang J; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Maru DM; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Maeda DY; Syntrix Pharmaceuticals, Auburn, WA 98001, USA.
  • Zebala JA; Syntrix Pharmaceuticals, Auburn, WA 98001, USA.
  • Kopetz S; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
  • Wang YA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: yalanwang@mdanderson.org.
  • DePinho RA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: rdepinho@mdanderson.org.
Cancer Cell ; 35(4): 559-572.e7, 2019 04 15.
Article em En | MEDLINE | ID: mdl-30905761
ABSTRACT
The biological functions and mechanisms of oncogenic KRASG12D (KRAS∗) in resistance to immune checkpoint blockade (ICB) therapy are not fully understood. We demonstrate that KRAS∗ represses the expression of interferon regulatory factor 2 (IRF2), which in turn directly represses CXCL3 expression. KRAS∗-mediated repression of IRF2 results in high expression of CXCL3, which binds to CXCR2 on myeloid-derived suppressor cells and promotes their migration to the tumor microenvironment. Anti-PD-1 resistance of KRAS∗-expressing tumors can be overcome by enforced IRF2 expression or by inhibition of CXCR2. Colorectal cancer (CRC) showing higher IRF2 expression exhibited increased responsiveness to anti-PD-1 therapy. The KRAS∗-IRF2-CXCL3-CXCR2 axis provides a framework for patient selection and combination therapies to enhance the effectiveness of ICB therapy in CRC.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Proteínas Proto-Oncogênicas p21(ras) / Evasão Tumoral / Resistencia a Medicamentos Antineoplásicos / Fator Regulador 2 de Interferon / Receptor de Morte Celular Programada 1 / Antineoplásicos Imunológicos Idioma: En Ano de publicação: 2019 Tipo de documento: Article
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Colorretais / Proteínas Proto-Oncogênicas p21(ras) / Evasão Tumoral / Resistencia a Medicamentos Antineoplásicos / Fator Regulador 2 de Interferon / Receptor de Morte Celular Programada 1 / Antineoplásicos Imunológicos Idioma: En Ano de publicação: 2019 Tipo de documento: Article