Abstract P3-05-04: AKT antagonist AZD5363 targets estrogen receptor (ER) function in endocrine resistant breast cancer (BC) and synergises with fulvestrant in vivo
Bibliographic record
Abstract
Abstract AIM: To evaluate the efficacy and functional consquences of combining AZD5363 with endocrine therapy in pre-clinical models of endocrine-sensitive and resistant ER+ BC. BACKGROUND: The PI3K/AKT/mTOR signalling pathway plays an important role in BC. Its close interaction with ER signalling becomes more complex and inter-dependent with acquisition of endocrine resistance. Targeting the mTOR pathway in combination with endocrine therapy has shown clinical utility. However, a negative feedback loop exists downstream of the PI3K/AKT/mTOR pathway with mTOR inhibition leading to increased activation of IGFR1-dependent AKT activity potentially negating long-term benefit. Direct blockade of AKT in combination with endocrine therapy, may provide a better rationale for treatment of endocrine-resistant BC, impacting on both cell survival/apoptosis and ER ligand-independent signaling. In this investigation, we assessed the efficacy of AZD5363, a pan-AKT inhibitor with endocrine therapies in pre-clinical models of endocrine sensitive and resistant ER+ BC and its impact on molecular and cellular response. METHODS: Inhibition of AKT using AZD5363 was examined in 5 ER+ BC lines before and after adaptation to long-term estrogen deprivation (LTED) or tamoxifen (TAMR). The effects of AZD5363 on cell proliferation were determined alone and in combination with endocrine treatment and feedback upregulation and activation of receptor tyrosine kinases (RTKs) was examined by western blotting. ER-transactivation was measured with an estrogen-response element (ERE)-linked luciferase reporter construct and confirmed using chromatin-immunoprecipitation. Global gene expression analysis was used to identify pathways associated with response. Xenografts were treated with AZD5363 ± fulvestrant to determine in vivo effects. RESULTS: AZD5363 caused a dose-dependent decrease in proliferation in all cell lines tested (GI50<500nM) with the exception of HCC1428-wild-type and LTED. Of note both T47D-LTED and ZR75-LTED, which lose expression of ER were exquisitely sensitive (GI50∼100nM). AZD5363 re-sensitised the TAMR cell line to tamoxifen and acted synergistically with fulvestrant in MCF7-Wt and MCF7-LTED (CI<1). AZD5363 decreased phosphorylation of AKT/mTOR substrates PRAS40, p70S6 and S6 in all cell lines tested and caused a significant decrease in phosphorylation of ERser167 with an associated 50% reduction in ERα-mediated transcription and decrease in recruitment of ER and CBP to ERE on the TFF1 promoter. Furthermore, AZD5363 reduced Rb and cyclinD1. Inhibition of AKT with AZD5363 resulted in upregulation and activation of RTKs, including IGF-IR, EGFR, ERBB2 and ERBB3, which was cell line specific. Global gene expression and pathway analysis of MCF7 and MCF7-LTED treated with AZD5363 highlighted the relevance of ERBB2-ERBB3, ERK5 and IGF1 signalling as potential feedback loops. Combined treatment with AZD5363 and fulvestrant showed strong synergy in an MCF7 xenograft. CONCLUSION: These data suggest that AZD5363 plus fulvestrant may be effective in BC that is sensitive or resistant to E-deprivation or tamoxifen and that activated AKT is a determinant of response. These data strongly support the need for clinical evaluation. Citation Format: Lesley-Ann Martin, Stephanie K Guest, Sunil Pancholi, Ricardo Ribas, Qiong Gao, Nikiana Simigdala, Aradhana Rani, Barry Davies, Stephen Johnston, Mitch Dowsett. AKT antagonist AZD5363 targets estrogen receptor (ER) function in endocrine resistant breast cancer (BC) and synergises with fulvestrant in vivo [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-04.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".