Your browser doesn't support javascript.
loading
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
ABSTRACT
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.
Assuntos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

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 Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

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 Ano de publicação: 2023 Tipo de documento: Article