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PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer.
Long, Li-Li; Ma, Si-Cong; Guo, Ze-Qin; Zhang, Yan-Pei; Fan, Zhenzhen; Liu, Li-Juan; Liu, Li; Han, Duan-Duan; Leng, Meng-Xin; Wang, Jian; Guo, Xue-Jun; Tan, Jia-Le; Cai, Xiao-Ting; Lin, Yan; Pan, Xinghua; Wu, De-Hua; Bai, Xue; Dong, Zhong-Yi.
Afiliación
  • Long LL; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Ma SC; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Guo ZQ; Information Management and Big Data Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Zhang YP; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Fan Z; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Liu LJ; Information Management and Big Data Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Liu L; Institute of Life and Health Engineering, Jinan University, Guangzhou, China.
  • Han DD; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, China.
  • Leng MX; Information Management and Big Data Center, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Wang J; Department of Medical Quality Management, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Guo XJ; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Tan JL; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Cai XT; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Lin Y; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Pan X; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Wu DH; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Bai X; Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
  • Dong ZY; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University, and Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, China.
Cancer Res ; 83(4): 568-581, 2023 02 15.
Article en En | MEDLINE | ID: mdl-36512628
Contradictory characteristics of elevated mutational burden and a "cold" tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically "hot" TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC. SIGNIFICANCE: Targeting PARP exerts dual effects to overcome LKB1 loss-driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Inmunidad Adaptativa / Inhibidores de Poli(ADP-Ribosa) Polimerasas / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cancer Res Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Pulmón de Células no Pequeñas / Inmunidad Adaptativa / Inhibidores de Poli(ADP-Ribosa) Polimerasas / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cancer Res Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos