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

Sep 23, 2026

Uploaded by hdkawk

Hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer makes up about 70% of cases, and resistance to current CDK4/6 inhibitor regimens frequently develops through activation of the PI3K-AKT-mTOR signaling pathway. Genetic drivers include PIK3CA mutations (~45%), AKT1 alterations, and PTEN loss, contributing to endocrine resistance and worse outcomes. This review synthesizes emerging PI3K/AKT/mTOR-targeted strategies, including isoform-specific PI3K inhibitors, AKT inhibitors, and mTOR inhibition, highlighting efficacy, tolerability trade-offs, sequencing challenges, and biomarker-guided selection.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Abstract

Key Points

Introduction

Epidemiology and clinical context

Scope and methods of the review

Drugs (2026) 86:1471–1487 [https://doi.org/10.1007/s40265-026-02347-5](https://doi.org/10.1007/s40265-026-02347-5) Emerging Strategies Targeting the PI3K/AKT/mTOR Pathway in HR+/ HER2– Advanced Breast Cancer Lan Lei1 · Madison Canning1 · Elizabeth Sakach1 · Almeera Lateef2 · Larisa Kamga2 · Minaam Abid3 · Kevin Kalinsky1 · Shipra Gandhi1 Received: 14 December 2025 / Accepted: 15 May 2026 / Published online: 28 July 2026 © The Author(s) 2026 Abstract Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer accounts for approximately 70% of breast cancer cases. Despite recent advances with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), resistance inevitably develops, often driven by activation of the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway. Genetic alterations such as PIK3CA mutations (present in ~ 45% of HR+/ HER2-tumors), AKT1 mutations, and PTEN loss contribute to endocrine resistance and poor outcomes. This review summarizes emerging strategies targeting this pathway to overcome resistance in advanced disease. Isoform-specific PI3K inhibitors, including alpelisib and inavolisib, have demonstrated clinically meaningful progression-free survival benefits in PIK3CA-mutated populations, with inavolisib showing improved tolerability and efficacy. In contrast, pan-PI3K inhibitors such as buparlisib have been constrained by toxicity. Targeting downstream signaling, AKT inhibitors have also shown benefit: capivasertib has demonstrated clinical efficacy leading to US Food and Drug Administration approval, while ipatasertib has yielded encouraging results, particularly in tumors harboring PIK3CA, AKT1, or PTEN alterations. Mammalian target of rapamycin inhibitors, notably everolimus, have shown efficacy irrespective of mutation status. The dual PI3KmTOR inhibitor (gedatolisib) has also shown promising progression-free survival benefit in a PIK3CA wild-type population. Next-generation agents, including mutant-selective PI3Kα inhibitors and bi-steric mTOR complex 1 inhibitors, are under active investigation. Optimal sequencing of these agents alongside endocrine therapy and CDK4/6i options remain a critical question, as does integration of genomic testing to guide therapy. Future directions include rational combination strategies, improved biomarker-driven selection, and novel modalities such as proteolysis-targeting chimeras (PROTACs) . Collectively, these advances aim to enhance durability of response, minimize toxicity, and improve survival in HR+/HER2-metastatic breast cancer. * Shipra Gandhi [shipra.gandhi@emory.edu](shipra.gandhi@emory.edu) 1 Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, 1365c Clifton Road, Atlanta, GA 30322-0001, USA 2 Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA 3 Department of Internal Medicine, Shifa International Hospital, Islamabad, Pakistan Key Points Endocrine therapy combined with cyclin-dependent kinase 4/6 inhibitors remains the standard first-line treatment for endocrine-sensitive hormone receptorpositive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. In endocrine-resistant disease, the addition of inavolisib to fulvestrant and palbociclib represents a new standard of care; however, both estrogen receptor-dependent and estrogen receptor-independent resistance mechanisms continue to necessitate the development of targeted therapeutic strategies. The phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway is a pivotal driver of endocrine resistance in HR+/HER2-breast cancer, underscoring its significance as a therapeutic target for combination strategies aimed at improving clinical outcomes. Future strategies include next-generation PI3K-AKTmTOR inhibitors, dual inhibitors, rational combinations with immunotherapy, and novel approach

FAQs

Why is the PI3K/AKT/mTOR pathway important in HR+/HER2- advanced breast cancer?

It is a pivotal driver of endocrine resistance in HR+/HER2- disease, making it a central target for combination strategies aimed at improving outcomes.

What genetic alterations are linked to resistance in HR+/HER2- tumors?

PIK3CA mutations (~45%), AKT1 mutations, and PTEN loss contribute to endocrine resistance and poor outcomes.

Which emerging PI3K/AKT/mTOR approaches are discussed as potential options?

The review covers isoform-specific and dual PI3K/mTOR strategies, AKT inhibitors such as capivasertib and ipatasertib, and mTOR inhibition such as everolimus, alongside next-generation agents and rational combinations.

Sep 23, 2026

Uploaded by hdkawk