期刊
NPJ BREAST CANCER
卷 6, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41523-020-00189-2
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资金
- Quantum Leap Healthcare Collaborative, FNIH, NCI [P01 CA210961]
- Safeway
- Albertsons Company
- William K. Bowes, Jr. Foundation
- Breast Cancer Research Foundation
- UCSF
- GMU
- Gateway for Cancer Research [G-16-900]
- Biomarkers Consortium
- Salesforce
- OpenClinica
- Formedix
- Natera
- Hologic Inc.
- TGen
- Illumina
- CCS Associates
- Berry Consultants
- Breast Cancer Research - Atwater Trust
- Stand up to Cancer
- California Breast Cancer Research Program
- Give Breast Cancer the Boot
- IQVIA
- Genentech
- Amgen
- Pfizer
- Merck
- Seattle Genetics
- Daiichi Sankyo
- AstraZeneca
- Dynavax Technologies
- Puma Biotechnology
- Plexxikon
- AbbVie
- Madrigal Pharmaceuticals
- Regeneron
- Agendia
The AKT inhibitor MK2206 (M) was evaluated in I-SPY 2 and graduated in the HER2+, HR-, and HR- HER2+ signatures. We hypothesized that AKT signaling axis proteins/genes may specifically predict response to M and tested 26 phospho-proteins and 10 genes involved in AKT-mTOR-HER signaling; in addition, we tested 9 genes from a previous study in the metastatic setting. One hundred and fifty patients had gene expression data from pretreatment biopsies available for analysis (M: 94, control: 56) and 138 had protein data (M: 87, control: 51). Logistic modeling was used to assess biomarker performance in pre-specified analysis. In general, phospho-protein biomarkers of activity in the AKT-mTOR-HER pathway appeared more predictive of response to M than gene expression or total protein biomarkers in the same pathway; however, the nature of the predictive biomarkers differed in the HER2+ and TN groups. In the HER2+ subset, patients achieving a pCR in M had higher levels of multiple AKT kinase substrate phospho-proteins (e.g., pmTOR, pTSC2). In contrast, in the TN subset responding patients had lower levels of AKT pathway phospho-proteins, such as pAKT, pmTOR, and pTSC2. Pathway mutations did not appear to account for these associations. Additional exploratory whole-transcriptome analysis revealed immune signaling as strongly associated with response to M in the HER2+ subset. While our sample size is small, these results suggest that the measurement of particular AKT kinase substrate phospho-proteins could be predictive of MK2206 efficacy in both HER2+ and TN tumors and that immune signaling may play a role in response in HER2+ patients.
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