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Targeting TBK1 to overcome resistance to cancer immunotherapy.
Sun, Yi; Revach, Or-Yam; Anderson, Seth; Kessler, Emily A; Wolfe, Clara H; Jenney, Anne; Mills, Caitlin E; Robitschek, Emily J; Davis, Thomas G R; Kim, Sarah; Fu, Amina; Ma, Xiang; Gwee, Jia; Tiwari, Payal; Du, Peter P; Sindurakar, Princy; Tian, Jun; Mehta, Arnav; Schneider, Alexis M; Yizhak, Keren; Sade-Feldman, Moshe; LaSalle, Thomas; Sharova, Tatyana; Xie, Hongyan; Liu, Shuming; Michaud, William A; Saad-Beretta, Rodrigo; Yates, Kathleen B; Iracheta-Vellve, Arvin; Spetz, Johan K E; Qin, Xingping; Sarosiek, Kristopher A; Zhang, Gao; Kim, Jong Wook; Su, Mack Y; Cicerchia, Angelina M; Rasmussen, Martin Q; Klempner, Samuel J; Juric, Dejan; Pai, Sara I; Miller, David M; Giobbie-Hurder, Anita; Chen, Jonathan H; Pelka, Karin; Frederick, Dennie T; Stinson, Susanna; Ivanova, Elena; Aref, Amir R; Paweletz, Cloud P; Barbie, David A.
Afiliação
  • Sun Y; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Revach OY; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Anderson S; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Kessler EA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wolfe CH; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Jenney A; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.
  • Mills CE; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.
  • Robitschek EJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Davis TGR; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Kim S; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Fu A; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Ma X; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Gwee J; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Tiwari P; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Du PP; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Sindurakar P; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Tian J; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Mehta A; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Schneider AM; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Yizhak K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Sade-Feldman M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • LaSalle T; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
  • Sharova T; Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Institute of Technology, Technion, Haifa, Israel.
  • Xie H; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Liu S; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Michaud WA; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Saad-Beretta R; Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Yates KB; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Iracheta-Vellve A; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.
  • Spetz JKE; Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA.
  • Qin X; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Sarosiek KA; Massachusetts General Hospital Cancer Center, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • Zhang G; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Kim JW; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Su MY; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.
  • Cicerchia AM; Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA.
  • Rasmussen MQ; John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA.
  • Klempner SJ; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.
  • Juric D; Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA.
  • Pai SI; John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA.
  • Miller DM; Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, MA, USA.
  • Giobbie-Hurder A; Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA.
  • Chen JH; John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA.
  • Pelka K; Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA, USA.
  • Frederick DT; Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University School of Medicine, Durham, NC, USA.
  • Stinson S; Preston Robert Tisch Brain Tumor Center, Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
  • Ivanova E; Moores Cancer Center, UC San Diego, La Jolla, CA, USA.
  • Aref AR; Center for Novel Therapeutics, UC San Diego, La Jolla, CA, USA.
  • Paweletz CP; Department of Medicine, UC San Diego, La Jolla, CA, USA.
  • Barbie DA; Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Nature ; 615(7950): 158-167, 2023 03.
Article em En | MEDLINE | ID: mdl-36634707
Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. Here we identify the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune-evasion gene in a pooled genetic screen4. Using a suite of genetic and pharmacological tools across multiple experimental model systems, we confirm a role for TBK1 as an immune-evasion gene. Targeting TBK1 enhances responses to PD-1 blockade by decreasing the cytotoxicity threshold to effector cytokines (TNF and IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids and matched patient-derived organoids. Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF and IFNγ in a JAK-STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is an effective strategy to overcome resistance to cancer immunotherapy.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Serina-Treonina Quinases / Resistencia a Medicamentos Antineoplásicos / Evasão da Resposta Imune / Imunoterapia Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Nature Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas Serina-Treonina Quinases / Resistencia a Medicamentos Antineoplásicos / Evasão da Resposta Imune / Imunoterapia Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Nature Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos