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Direct targeting of amplified gene loci for proapoptotic anticancer therapy.
Kaushik Tiwari, Meetu; Colon-Rios, Daniel A; Tumu, Hemanta C Rao; Liu, Yanfeng; Quijano, Elias; Krysztofiak, Adam; Chan, Cynthia; Song, Eric; Braddock, Demetrios T; Suh, Hee-Won; Saltzman, W Mark; Rogers, Faye A.
Afiliação
  • Kaushik Tiwari M; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA.
  • Colon-Rios DA; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA.
  • Tumu HCR; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA.
  • Liu Y; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA.
  • Quijano E; Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
  • Krysztofiak A; Department of Biomedical Engineering, Yale School of Medicine, New Haven, CT, USA.
  • Chan C; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA.
  • Song E; Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, USA.
  • Braddock DT; Department of Biomedical Engineering, Yale School of Medicine, New Haven, CT, USA.
  • Suh HW; Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
  • Saltzman WM; Department of Biomedical Engineering, Yale School of Medicine, New Haven, CT, USA.
  • Rogers FA; Department of Biomedical Engineering, Yale School of Medicine, New Haven, CT, USA.
Nat Biotechnol ; 40(3): 325-334, 2022 03.
Article em En | MEDLINE | ID: mdl-34711990
Gene amplification drives oncogenesis in a broad spectrum of cancers. A number of drugs have been developed to inhibit the protein products of amplified driver genes, but their clinical efficacy is often hampered by drug resistance. Here, we introduce a therapeutic strategy for targeting cancer-associated gene amplifications by activating the DNA damage response with triplex-forming oligonucleotides (TFOs), which drive the induction of apoptosis in tumors, whereas cells without amplifications process lower levels of DNA damage. Focusing on cancers driven by HER2 amplification, we find that TFOs targeting HER2 induce copy number-dependent DNA double-strand breaks (DSBs) and activate p53-independent apoptosis in HER2-positive cancer cells and human tumor xenografts via a mechanism that is independent of HER2 cellular function. This strategy has demonstrated in vivo efficacy comparable to that of current precision medicines and provided a feasible alternative to combat drug resistance in HER2-positive breast and ovarian cancer models. These findings offer a general strategy for targeting tumors with amplified genomic loci.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Amplificação de Genes Idioma: En Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Amplificação de Genes Idioma: En Ano de publicação: 2022 Tipo de documento: Article País de afiliação: Estados Unidos