Your browser doesn't support javascript.
loading
Targeting activated PI3K/mTOR signaling overcomes acquired resistance to CDK4/6-based therapies in preclinical models of hormone receptor-positive breast cancer.
O'Brien, Neil A; McDermott, Martina S J; Conklin, Dylan; Luo, Tong; Ayala, Raul; Salgar, Suruchi; Chau, Kevin; DiTomaso, Emmanuelle; Babbar, Naveen; Su, Faye; Gaither, Alex; Hurvitz, Sara A; Linnartz, Ronald; Rose, Kristine; Hirawat, Samit; Slamon, Dennis J.
Afiliação
  • O'Brien NA; Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • McDermott MSJ; Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Conklin D; Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Luo T; Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Ayala R; Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Salgar S; Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Chau K; Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • DiTomaso E; Novartis Pharmaceuticals, Cambridge, MA, USA.
  • Babbar N; Currently Bayer Pharmaceuticals, Boston, MA, USA.
  • Su F; Novartis Pharmaceuticals, Cambridge, MA, USA.
  • Gaither A; Novartis Pharmaceuticals, Cambridge, MA, USA.
  • Hurvitz SA; Novartis Pharmaceuticals, Cambridge, MA, USA.
  • Linnartz R; Currently LG Life Sciences, Cambridge, MA, USA.
  • Rose K; Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
  • Hirawat S; Novartis Pharmaceuticals, Cambridge, MA, USA.
  • Slamon DJ; Novartis Pharmaceuticals, Cambridge, MA, USA.
Breast Cancer Res ; 22(1): 89, 2020 08 14.
Article em En | MEDLINE | ID: mdl-32795346
BACKGROUND: Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2- breast cancer. However, acquired resistance to these therapies frequently leads to disease progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance. METHODS: In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance. RESULTS: We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2- breast cancer models. CONCLUSIONS: These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2- breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.
Assuntos
Palavras-chave

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Resistencia a Medicamentos Antineoplásicos / Fosfatidilinositol 3-Quinases / Receptor alfa de Estrogênio / Quinase 4 Dependente de Ciclina / Quinase 6 Dependente de Ciclina / Serina-Treonina Quinases TOR Limite: Animals / Female / Humans / Pregnancy Idioma: En Revista: Breast Cancer Res Assunto da revista: NEOPLASIAS Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Resistencia a Medicamentos Antineoplásicos / Fosfatidilinositol 3-Quinases / Receptor alfa de Estrogênio / Quinase 4 Dependente de Ciclina / Quinase 6 Dependente de Ciclina / Serina-Treonina Quinases TOR Limite: Animals / Female / Humans / Pregnancy Idioma: En Revista: Breast Cancer Res Assunto da revista: NEOPLASIAS Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Estados Unidos