Cutano Valentina, Chia Ming Li, Wigmore Eleanor M, Hopcroft Lorna, Williamson Stuart C, Christie Amanda L, Willis Brandon, Kerr James, Ashforth Jenny, Fox Rhys, D'Arcy Sophie, Bradshaw Lauren, Blaker Catherine, Eberlein Cath, Montava-Garriga Lambert, de Bruin Elza C, Critchlow Susan E, Brindle Kevin M, Barry Simon T, Ros Susana
Bioscience, Early Oncology, AstraZeneca, Cambridge, UK.
Cancer Research UK Cambridge Institute, Cambridge, UK.
NPJ Breast Cancer. 2025 Apr 22;11(1):36. doi: 10.1038/s41523-025-00752-9.
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.
通过纯合或半合子缺失导致的PTEN表达缺失在PIK3CA突变的ER+乳腺癌肿瘤中很常见。我们评估了PTEN蛋白表达降低对PIK3CA改变的肿瘤中AKT抑制剂卡匹西他滨疗效的影响。在PIK3CA改变、PTEN蛋白高表达的模型中，PI3Kα和AKT抑制有效，然而单独或与氟维司群联合使用时，PTEN缺失和部分PTEN表达降低会减弱PI3Kα抑制剂的疗效，但不会减弱AKT抑制剂的疗效。疗效依赖于FOXO3且与FOXM1下调相关。FOXO3A缺失会降低对卡匹西他滨的反应，并增加FOXM1表达。长期将ER+乳腺癌细胞暴露于卡匹西他滨会上调FOXM1表达。下调FOXM1表达可逆转对卡匹西他滨的耐药性，而FOXM1过表达则会降低卡匹西他滨的疗效。总体而言，这表明AKT-FOXO3-FOXM1轴在伴有或不伴有PTEN表达的PIK3CA突变的ER+乳腺癌对AKT抑制剂的反应中起关键作用，FOXO3表达缺失可介导耐药性，且FOXM1下调是反应的潜在生物标志物。
