Mechanism of action biomarkers predicting response to AKT inhibition in the I-SPY 2 breast cancer trial

• Published in: NPJ breast cancer Vol. 6; no. 1; p. 48
• Main Authors: Wolf, Denise M., Yau, Christina, Wulfkuhle, Julia, Brown-Swigart, Lamorna, Gallagher, Rosa I., Jesus M. Magbanua, Mark, O’Grady, Nick, Hirst, Gillian, Asare, Smita, Tripathy, Debu, Berry, Don, Esserman, Laura, Chien, A. Jo, Petricoin, Emanuel F., van ‘t Veer, Laura
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.10.2020; Nature Publishing Group
• Subjects: 692/53/2423; 692/699/67/1347; Biomarkers; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cell Biology; Gene expression; Human Genetics; Kinases; Oncology; Proteins; Breast cancer; Predictive markers
• ISSN: 2374-4677; 2374-4677
• DOI: 10.1038/s41523-020-00189-2

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.