Scholarlink

<p>Loss of PTEN expression, via homozygous or hemizygous deletion, is common in <i>PIK3CA</i> mutant ER + BC tumors. We assessed reduction of PTEN protein expression on AKT inhibitor capivasertib efficacy in <i>PIK3CA</i> altered tumors. In <i>PIK3CA</i> altered, PTEN protein high models, PI3Kα and AKT inhibition was effective, however ablation and partial PTEN expression reduction attenuated PI3Kαi but not AKTi efficacy, alone or combined with fulvestrant. Efficacy was FOXO3 dependent and associated with FOXM1 downregulation. FOXO3A deletion reduced response to capivasertib, and increased FOXM1 expression. Long term capivasertib exposure of ER+ BC cells upregulated FOXM1 expression. Downregulating FOXM1 expression reversed resistance to capivasertib, while FOXM1 overexpression reduced capivasertib efficacy. Collectively this suggests the AKT-FOXO3-FOXM1 axis plays a pivotal role in response to AKTi in ER+ breast cancer with <i>PIK3CA</i> mutations with and without expression of PTEN, that FOXO3 expression loss can mediate resistance, and that FOXM1 downregulation is a potential biomarker of response.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The interplay between FOXO3 and FOXM1 influences sensitivity to AKT inhibition in PIK3CA and PIK3CA/PTEN altered estrogen receptor positive breast cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年4月22日

查看全文
  • Valentina Cutano,
  • Ming Li Chia,
  • Eleanor M. Wigmore,
  • Lorna Hopcroft,
  • Stuart C. Williamson,
  • Amanda L. Christie,
  • Brandon Willis,
  • James Kerr,
  • Jenny Ashforth,
  • Rhys Fox,
  • Sophie D’Arcy,
  • Lauren Bradshaw,
  • Catherine Blaker,
  • Cath Eberlein,
  • Lambert Montava-Garriga,
  • Elza C. de Bruin,
  • Susan E. Critchlow,
  • Kevin M. Brindle,
  • Simon T. Barry,
  • Susana Ros

摘要

Loss of PTEN expression, via homozygous or hemizygous deletion, is common in PIK3CA mutant ER + BC tumors. We assessed reduction of PTEN protein expression on AKT inhibitor capivasertib efficacy in PIK3CA altered tumors. In PIK3CA altered, PTEN protein high models, PI3Kα and AKT inhibition was effective, however ablation and partial PTEN expression reduction attenuated PI3Kαi but not AKTi efficacy, alone or combined with fulvestrant. Efficacy was FOXO3 dependent and associated with FOXM1 downregulation. FOXO3A deletion reduced response to capivasertib, and increased FOXM1 expression. Long term capivasertib exposure of ER+ BC cells upregulated FOXM1 expression. Downregulating FOXM1 expression reversed resistance to capivasertib, while FOXM1 overexpression reduced capivasertib efficacy. Collectively this suggests the AKT-FOXO3-FOXM1 axis plays a pivotal role in response to AKTi in ER+ breast cancer with PIK3CA mutations with and without expression of PTEN, that FOXO3 expression loss can mediate resistance, and that FOXM1 downregulation is a potential biomarker of response.