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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
Summary
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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