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Targeting the PI3K/mTOR Pathway: Emerging Inhibitors and Therapeutic Strategies

Introduction

The PI3K/mTOR pathway is a critical signaling cascade involved in cell growth, proliferation, and survival. Dysregulation of this pathway is frequently observed in various cancers, making it an attractive target for therapeutic intervention. In recent years, significant progress has been made in developing inhibitors that target key components of this pathway, offering new hope for patients with malignancies driven by PI3K/mTOR aberrations.

The PI3K/mTOR Pathway: An Overview

The PI3K/mTOR pathway begins with the activation of phosphoinositide 3-kinase (PI3K), which phosphorylates phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). This lipid second messenger recruits Akt to the plasma membrane, where it is activated. Akt then phosphorylates numerous downstream targets, including mTOR, a central regulator of cell growth and metabolism.

mTOR exists in two distinct complexes: mTORC1 and mTORC2. While mTORC1 primarily regulates protein synthesis and autophagy, mTORC2 controls cell survival and cytoskeletal organization. The intricate interplay between these components makes the PI3K/mTOR pathway a complex but promising therapeutic target.

Current PI3K/mTOR Pathway Inhibitors

Several classes of inhibitors targeting different nodes of the PI3K/mTOR pathway have been developed:

1. PI3K Inhibitors

These compounds target the catalytic subunits of PI3K and include:

• Pan-PI3K inhibitors (e.g., Buparlisib, Pictilisib)
• Isoform-selective inhibitors (e.g., Alpelisib for PI3Kα, Idelalisib for PI3Kδ)
• Dual PI3K/mTOR inhibitors (e.g., Dactolisib, Voxtalisib)

2. AKT Inhibitors

Targeting this critical node downstream of PI3K includes compounds like:

• MK-2206 (allosteric inhibitor)
• Ipatasertib (ATP-competitive inhibitor)
• Capivasertib (pan-AKT inhibitor)

3. mTOR Inhibitors

These agents target the mTOR kinase and include:

• Rapalogs (e.g., Everolimus, Temsirolimus)
• ATP-competitive inhibitors (e.g., Sapanisertib, Vistusertib)

Therapeutic Strategies and Challenges

While PI3K/mTOR inhibitors show promise, several challenges must be addressed:

1. Combination Therapies

Combining pathway inhibitors with other targeted therapies or conventional chemotherapy has shown improved efficacy in preclinical models. Notable combinations include:

• PI3K inhibitors with endocrine therapy in breast cancer

Keyword: PI3K mTOR pathway inhibitors

• mTOR inhibitors with HER2-targeted agents
• AKT inhibitors with PARP inhibitors in BRCA-mutant cancers

2. Overcoming Resistance

Resistance mechanisms include:

• Feedback activation of parallel pathways (e.g., MAPK)
• Emergence of mutations in pathway components
• Compensatory upregulation of receptor tyrosine kinases</li