Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review

  title={Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review},
  author={Ricardo L. B. Costa and Hyo S Han and William John Gradishar},
  journal={Breast Cancer Research and Treatment},
PurposeTriple-negative breast cancer (TNBC) accounts for approximately 20% of breast cancer cases. [] Key Result In addition, new compounds with distinct specificity and potency targeting different PI3K/AKT/mTOR components and cognate molecules (e.g., mitogen-activated protein kinase) are being developed. These agents present a wide range of toxicity profiles and early efficacy signals, which must be considered prior to the advancement of new agents in later-phase clinical trials.ConclusionsThe development…
Triple-Negative Breast Cancer: The Progress of Targeted Therapies and Future Tendencies
Clinical studies published within the last five years are presented in order to reveal possible targeted therapies against triple-negative breast cancer and the PI3K/AKT/mTOR pathway seems to be a promising field for the development of new anti-TNBC targeted therapies.
Alpelisib in the Treatment of Breast Cancer: A Short Review on the Emerging Clinical Data
The development of PI3K inhibitor alpelisib is discussed, indications for use in HR+/HER2 negative MBC, safety and tolerability and the future direction of this therapy in the treatment of breast cancer are discussed.
Co-targeting EGFR and mTOR with gefitinib and everolimus in triple-negative breast cancer cells
Gene and protein expression analysis revealed significant downregulation of cell cycle regulators after exposure to combined treatment, suggesting that dual inhibition of mTOR and EGFR may be an effective treatment for TNBC with activating mutations of PI3K.
Dual Target of EGFR and mTOR Suppress Triple Negative Breast Cancer Cell Growth Via Regulation The Phosphorylation of mTOR Downstream Proteins
Background:Triple-negative breast cancers (TNBC) are the most aggressive subtype of breast cancer, accounting for 15% - 20% of all cases, and have no response to available hormonal therapies and
Multi-targeted kinase inhibition alleviates mTOR inhibitor resistance in triple-negative breast cancer
As single rapalog treatment is insufficient to block mTOR signaling in rapalog-resistant TNBC cells, the results provide a potential multi-kinase inhibitor combinatorial strategy to overcome mTOR-targeted therapy resistance in T NBC cells.
Moving Towards Targeted Therapies for Triple-Negative Breast Cancer
Various novel targeted agents as monotherapy, dual-targeted combinations, and chemotherapy combinations are currently under investigation and the results are promising and may significantly improve patient outcomes in TNBC.
PI3K/ Akt/ mTOR pathway as a therapeutic target for colorectal cancer: A review of preclinical and clinical evidence.
Inhibitors of the PI3K/Akt/mTOR pathway has been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.
Emerging Therapeutics for Patients with Triple-Negative Breast Cancer
The aim of this review is to provide an overview on the emerging therapeutics for TNBC, describing both previously approved therapies that are currently being repurposed, as well as new target therapies that may improve patient outcomes.


Targeting the PI3K/AKT/mTOR Pathway for the Treatment of Mesenchymal Triple-Negative Breast Cancer: Evidence From a Phase 1 Trial of mTOR Inhibition in Combination With Liposomal Doxorubicin and Bevacizumab
To assess safety and efficacy of mammalian target of rapamycin (mTOR) inhibition in combination with liposomal doxorubicin and bevacizumab in patients with advanced metaplastic TNBC, a Phase 1 study with dose escalation and dose expansion at the University of Texas MD Anderson Cancer Center found DAT and DAE had notable activity in mesenchymal TNBC.
Targeting mTOR pathway inhibits tumor growth in different molecular subtypes of triple-negative breast cancers
Targeting mTOR decreased tumor growth in 7 out of 15 TNBC PDX tested and response to everolimus occurred in different TNBC subtypes and was associated with post-treatment increase of P-AKT.
Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition
A panel of patient-derived xenograft models covering a spectrum of TNBC subtypes was generated that histologically and genomically matched original patient tumors, suggesting that mTOR inhibitors can be effective in TNBC, but will require use with additional therapies, warranting investigation of optimal drug combinations.
Inhibition of the PI3K/AKT/mTOR Pathway in Solid Tumors.
  • P. LoRusso
  • Biology
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 2016
To maximize therapeutic benefit, drug combinations and schedules must be explored to identify those with the highest efficacy and lowest toxicity overlap, and defining appropriate patient subpopulations, for both monotherapy and drug combinations, will be important.
Combined Targeting of mTOR and AKT Is an Effective Strategy for Basal-like Breast Cancer in Patient-Derived Xenograft Models
The results provide a preclinical rationale for future clinical investigation of this combination in basal-like breast cancer with loss of PTEN and a synergistic effect of these two agents on tumor volume was observed in WU-BC3 with PTEN knockdown.
Phosphorylated mTOR expression correlates with poor outcome in early-stage triple negative breast carcinomas.
In patients at stage 1 and 2 disease, those with p-mTOR expression had significantly worse overall as well as recurrence-free survival compared to those without p- mTOR expression.
Abstract P3-03-15: Synergistic suppression of triple negative breast cancer with the combination of PI3K inhibitor (alpelisib, BYL719) and CDK inhibitor (ribociclib, LEE011)
It is demonstrated that alpelisib plus ribociclib can synergistically enhance suppression of BC across multiple subtypes of TNBC.
Analysis of PIK3CA Mutations and Activation Pathways in Triple Negative Breast Cancer
The data shows that PIK3CA mutations and PI3K/AKT pathway activation are common events in TNBC, and a deeper investigation on specific TNBC genomic abnormalities might be helpful to select patients who would benefit from current targeted therapy strategies.
Drug discovery approaches targeting the PI3K/Akt pathway in cancer
This review summarizes current preclinical knowledge of modulators of the PI3K/Akt pathway in which drug discovery and development activities have been advanced focusing on both the relevant clinical stage inhibitors and other disclosed tool compounds targetingPI3K, PDK1, Akt and HSP90.