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Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer.
Faber, Anthony C; Farago, Anna F; Costa, Carlotta; Dastur, Anahita; Gomez-Caraballo, Maria; Robbins, Rebecca; Wagner, Bethany L; Rideout, William M; Jakubik, Charles T; Ham, Jungoh; Edelman, Elena J; Ebi, Hiromichi; Yeo, Alan T; Hata, Aaron N; Song, Youngchul; Patel, Neha U; March, Ryan J; Tam, Ah Ting; Milano, Randy J; Boisvert, Jessica L; Hicks, Mark A; Elmiligy, Sarah; Malstrom, Scott E; Rivera, Miguel N; Harada, Hisashi; Windle, Brad E; Ramaswamy, Sridhar; Benes, Cyril H; Jacks, Tyler; Engelman, Jeffrey A.
Afiliação
  • Faber AC; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; acfaber@vcu.edu jengelman@partners.org.
  • Farago AF; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
  • Costa C; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Dastur A; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Gomez-Caraballo M; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Robbins R; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
  • Wagner BL; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
  • Rideout WM; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
  • Jakubik CT; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Ham J; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Edelman EJ; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Ebi H; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Yeo AT; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Hata AN; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Song Y; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Patel NU; Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298; and.
  • March RJ; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Tam AT; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Milano RJ; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Boisvert JL; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Hicks MA; Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298; and.
  • Elmiligy S; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
  • Malstrom SE; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
  • Rivera MN; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114.
  • Harada H; Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298; and.
  • Windle BE; Philips Institute for Oral Health Research, Virginia Commonwealth University School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298; and.
  • Ramaswamy S; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Benes CH; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115;
  • Jacks T; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02138;
  • Engelman JA; Massachusetts General Hospital Cancer Center, Boston, MA 02129; Department of Medicine, Harvard Medical School, Boston, MA 02115; acfaber@vcu.edu jengelman@partners.org.
Proc Natl Acad Sci U S A ; 112(11): E1288-96, 2015 Mar 17.
Article em En | MEDLINE | ID: mdl-25737542
BH3 mimetics such as ABT-263 induce apoptosis in a subset of cancer models. However, these drugs have shown limited clinical efficacy as single agents in small-cell lung cancer (SCLC) and other solid tumor malignancies, and rational combination strategies remain underexplored. To develop a novel therapeutic approach, we examined the efficacy of ABT-263 across >500 cancer cell lines, including 311 for which we had matched expression data for select genes. We found that high expression of the proapoptotic gene Bcl2-interacting mediator of cell death (BIM) predicts sensitivity to ABT-263. In particular, SCLC cell lines possessed greater BIM transcript levels than most other solid tumors and are among the most sensitive to ABT-263. However, a subset of relatively resistant SCLC cell lines has concomitant high expression of the antiapoptotic myeloid cell leukemia 1 (MCL-1). Whereas ABT-263 released BIM from complexes with BCL-2 and BCL-XL, high expression of MCL-1 sequestered BIM released from BCL-2 and BCL-XL, thereby abrogating apoptosis. We found that SCLCs were sensitized to ABT-263 via TORC1/2 inhibition, which led to reduced MCL-1 protein levels, thereby facilitating BIM-mediated apoptosis. AZD8055 and ABT-263 together induced marked apoptosis in vitro, as well as tumor regressions in multiple SCLC xenograft models. In a Tp53; Rb1 deletion genetically engineered mouse model of SCLC, the combination of ABT-263 and AZD8055 significantly repressed tumor growth and induced tumor regressions compared with either drug alone. Furthermore, in a SCLC patient-derived xenograft model that was resistant to ABT-263 alone, the addition of AZD8055 induced potent tumor regression. Therefore, addition of a TORC1/2 inhibitor offers a therapeutic strategy to markedly improve ABT-263 activity in SCLC.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sulfonamidas / Protocolos de Quimioterapia Combinada Antineoplásica / Carcinoma de Pequenas Células do Pulmão / Compostos de Anilina / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2015 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Sulfonamidas / Protocolos de Quimioterapia Combinada Antineoplásica / Carcinoma de Pequenas Células do Pulmão / Compostos de Anilina / Neoplasias Pulmonares Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2015 Tipo de documento: Article