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Targeting MLL Methyltransferases Enhances the Antitumor Effects of PI3K Inhibition in Hormone Receptor-positive Breast Cancer.
Jones, Robert B; Farhi, Jonathan; Adams, Miranda; Parwani, Kiran K; Cooper, Garrett W; Zecevic, Milica; Lee, Richard S; Hong, Andrew L; Spangle, Jennifer M.
Afiliação
  • Jones RB; Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
  • Farhi J; Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
  • Adams M; Cancer Biology Graduate Program, Emory University School of Medicine, Atlanta, Georgia.
  • Parwani KK; Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
  • Cooper GW; Cancer Biology Graduate Program, Emory University School of Medicine, Atlanta, Georgia.
  • Zecevic M; Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
  • Lee RS; Cancer Biology Graduate Program, Emory University School of Medicine, Atlanta, Georgia.
  • Hong AL; Genetics and Molecular Biology Graduate Program, Emory University School of Medicine, Atlanta, Georgia.
  • Spangle JM; Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia.
Cancer Res Commun ; 2(12): 1569-1578, 2022 12.
Article em En | MEDLINE | ID: mdl-36970726
ABSTRACT
The high frequency of aberrant PI3K pathway activation in hormone receptor-positive (HR+) breast cancer has led to the development, clinical testing, and approval of the p110α-selective PI3K inhibitor alpelisib. The limited clinical efficacy of alpelisib and other PI3K inhibitors is partially attributed to the functional antagonism between PI3K and estrogen receptor (ER) signaling, which is mitigated via combined PI3K inhibition and endocrine therapy. We and others have previously demonstrated chromatin-associated mechanisms by which PI3K supports cancer development and antagonizes ER signaling through the modulation of the H3K4 methylation axis, inhibition of KDM5A promoter H3K4 demethylation and KMT2D/MLL4-directed enhancer H3K4 methylation. Here we show that inhibition of the H3K4 histone methyltransferase MLL1 in combination with PI3K inhibition impairs HR+ breast cancer clonogenicity and cell proliferation. While combined PI3K/MLL1 inhibition reduces PI3K/AKT signaling and H3K4 methylation, MLL1 inhibition increases PI3K/AKT signaling through the dysregulation of gene expression associated with AKT activation. These data reveal a feedback loop between MLL1 and AKT whereby MLL1 inhibition reactivates AKT. We show that combined PI3K and MLL1 inhibition synergizes to cause cell death in in vitro and in vivo models of HR+ breast cancer, which is enhanced by the additional genetic ablation of the H3K4 methyltransferase and AKT target KMT2D/MLL4. Together, our data provide evidence of a feedback mechanism connecting histone methylation with AKT and may support the preclinical development and testing of pan-MLL inhibitors.

Significance:

Here the authors leverage PI3K/AKT-driven chromatin modification to identify histone methyltransferases as a therapeutic target. Dual PI3K and MLL inhibition synergize to reduce clonogenicity and cell proliferation, and promote in vivo tumor regression. These findings suggest patients with PIK3CA-mutant, HR+ breast cancer may derive clinical benefit from combined PI3K/MLL inhibition.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Fosfatidilinositol 3-Quinases Tipo de estudo: Prognostic_studies Limite: Female / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Fosfatidilinositol 3-Quinases Tipo de estudo: Prognostic_studies Limite: Female / Humans Idioma: En Ano de publicação: 2022 Tipo de documento: Article