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Emerging Strategies Targeting the PI3K/AKT/mTOR Pathway in HR+/HER2- Advanced Breast Cancer

Lan Lei1, Madison Canning1, Elizabeth Sakach1

  • 1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365c Clifton Road, Atlanta, GA, 30322-0001, USA.

Drugs
|July 28, 2026
PubMed

Insights

Targeting the PI3K-AKT-mTOR pathway with novel inhibitors offers new hope for hormone receptor-positive, HER2-negative metastatic breast cancer patients resistant to CDK4/6 inhibitors. These strategies aim to improve outcomes by overcoming endocrine resistance and enhancing treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer is the most common subtype (~70%).
  • Resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is a significant clinical challenge, often driven by the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway.
  • Genetic alterations like PIK3CA mutations (~45% of HR+/HER2- tumors), AKT1 mutations, and PTEN loss are implicated in endocrine resistance and poorer prognoses.

Purpose of the Study:

  • To review emerging therapeutic strategies targeting the PI3K-AKT-mTOR pathway to overcome resistance in advanced HR+/HER2- breast cancer.
  • To summarize the clinical efficacy and tolerability of various inhibitors targeting different nodes of this pathway.
  • To discuss future directions, including combination strategies, biomarker selection, and novel therapeutic modalities.

Main Methods:

  • Review of preclinical and clinical data on targeted therapies for HR+/HER2- metastatic breast cancer.
  • Analysis of emerging agents including isoform-specific PI3K inhibitors, AKT inhibitors, mTOR inhibitors, and dual PI3K-mTOR inhibitors.
  • Discussion of genetic alterations (PIK3CA, AKT1, PTEN) and their role in treatment response and resistance.

Main Results:

  • Isoform-specific PI3K inhibitors (alpelisib, inavolisib) show PFS benefits in PIK3CA-mutated populations, with inavolisib demonstrating improved tolerability.
  • AKT inhibitors (capivasertib, ipatasertib) show clinical efficacy, particularly in tumors with PIK3CA, AKT1, or PTEN alterations; capivasertib is FDA-approved.
  • mTOR inhibitors (everolimus) are effective regardless of mutation status, and dual PI3K-mTOR inhibitors (gedatolisib) show promise in PIK3CA wild-type patients.

Conclusions:

  • Targeting the PI3K-AKT-mTOR pathway is a promising strategy to overcome resistance to CDK4/6i in HR+/HER2- metastatic breast cancer.
  • Next-generation agents and combination strategies are under investigation to optimize treatment sequencing and improve patient outcomes.
  • Integration of genomic testing and development of novel modalities like PROTACs are crucial for future therapeutic advancements.

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