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

Abstract

Purpose

Triple-negative breast cancer (TNBC) accounts for approximately 20% of breast cancer cases. Although there have been advances in the treatment of hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancers, targeted therapies for TNBC remain unavailable. In this narrative review, we summarize recent discoveries related to the underlying biology of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway in TNBC, examine clinical progress to date, and suggest rational future approaches for investigational therapies in TNBC.

Results

As with other subtypes of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are common in TNBC. Preclinical data support the notion that these aberrations predict TNBC inhibition by targeted agents. In a recently published phase 2 clinical trial, an AKT inhibitor (ipatasertib) improved outcomes in a subset of patients with metastatic TNBC when combined with paclitaxel in the first-line setting. 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.

Conclusions

The development of drugs targeting the PI3K/AKT/mTOR pathway for the treatment of TNBC is an evolving field that should take into account the efficacies and toxicities of new agents in addition to their interactions with different cancer pathways.

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Acknowledgements

We thank Sonya Smyk (Moffitt Cancer Center) for editorial assistance. She received no compensation beyond her regular salary.

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This research did not receive any specific grant funding from agencies in the public, commercial, or not-for-profit sectors.

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Correspondence to Ricardo L. B. Costa.

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Costa, R.L.B., Han, H.S. & Gradishar, W.J. Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review. Breast Cancer Res Treat 169, 397–406 (2018). https://doi.org/10.1007/s10549-018-4697-y

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Keywords

  • Triple-negative breast cancer
  • Targeted therapy
  • PI3K
  • mTOR