期刊
SCIENCE TRANSLATIONAL MEDICINE
卷 7, 期 283, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaa4442
关键词
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资金
- Stand Up To Cancer Dream Team Translational Cancer Research Grant, a program of the Entertainment Industry Foundation [SU2C-AACR-DT0209]
- Breast Cancer Research Foundation
- European Research Council [AdG09250244]
- Instituto de Salud Carlos III [PSO9/00623, FIS PI13/01714]
- Banco Bilbao Vizcaya Argentaria Foundation (Tumor Biomarker Research Program)
- Spanish Society of Medical Oncology
- GHD/FERO grant
- Louis Gerstner YIA
- Damon Runyon Foundation
- Bayer
- K99/R00 Pathway to Independence award [1K99CA181492-01A1]
- PHS [5R01 CA 025836]
- NATIONAL CANCER INSTITUTE [P30CA008748, P30CA016672, K99CA181492, R01CA025836, P01CA094060] Funding Source: NIH RePORTER
Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase alpha (PI3K alpha) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of up-regulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3K alpha inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3K alpha inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.
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