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AKT signaling in ERBB2-amplified breast cancer

F Javier Carmona1, Filippo Montemurro2, Srinivasaraghavan Kannan3

  • 1Memorial Sloan Kettering Cancer Center (MSKCC), Human Oncology and Pathogenesis Program (HOPP), NY, USA.

Pharmacology & Therapeutics
|December 10, 2015
PubMed

Insights

The PI3K/AKT pathway is crucial in ERBB2-amplified breast cancer, driving resistance to targeted therapies. Understanding its role and mutations like AKT3 can lead to better treatment strategies and durable responses.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The Phosphatidylinositol 3-Kinase/AKT (PI3K/AKT) pathway is a key signaling cascade implicated in various cancers.
  • Hyperactivation of this pathway contributes to therapeutic resistance in ERBB2-amplified breast cancer, often through compensatory mechanisms or genetic alterations.
  • ERBB2-targeted therapies are standard, but resistance necessitates understanding alternative signaling pathways.

Purpose of the Study:

  • To review the role of the PI3K/AKT pathway in ERBB2-amplified breast cancer pathogenesis.
  • To discuss current targeted agents for ERBB2-amplified breast cancer, focusing on AKT kinases.
  • To highlight genomics-based approaches for identifying novel therapeutic targets, exemplified by a new AKT3 mutation.

Main Methods:

  • Literature review of the PI3K/AKT pathway in breast cancer.
  • Analysis of targeted therapeutic agents for ERBB2-amplified breast cancer.
  • Presentation of preliminary data on a novel AKT3 mutation.

Main Results:

  • The PI3K/AKT pathway is integral to breast cancer development and resistance to ERBB2-targeted therapy.
  • Genomic alterations and compensatory mechanisms drive resistance to anti-ERBB2 agents.
  • A novel AKT3 mutation was identified in the context of resistance to anti-ERBB2 therapy.

Conclusions:

  • Combining anti-ERBB2 agents with PI3K/AKT inhibitors is a promising strategy to overcome resistance.
  • Identifying genomic alterations is crucial for designing clinical studies to prevent drug resistance and achieve durable responses.
  • Genomics-driven approaches can uncover novel actionable targets, such as the identified AKT3 mutation, for improved breast cancer treatment.
Keywords:
AKT3Drug resistancePI3KTargeted therapyTrastuzumabmTOR

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