# PI3K/mTOR Pathway Inhibitors: Current Advances and Therapeutic Applications

Introduction to the PI3K/mTOR Pathway

The PI3K/mTOR pathway is a crucial intracellular signaling network that regulates various cellular processes including growth, proliferation, metabolism, and survival. This pathway has gained significant attention in cancer research due to its frequent dysregulation in human malignancies. The pathway consists of phosphatidylinositol 3-kinase (PI3K), Akt (protein kinase B), and mammalian target of rapamycin (mTOR), forming a cascade that transmits signals from growth factors and nutrients to regulate cellular functions.

Mechanism of PI3K/mTOR Pathway Activation

Activation of the PI3K/mTOR pathway typically begins with growth factor receptor binding, which recruits and activates PI3K. PI3K then 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 becomes activated. Akt then phosphorylates numerous downstream targets, including mTOR, which exists in two distinct complexes: mTORC1 and mTORC2. These complexes regulate protein synthesis, cell growth, and metabolism through various effectors.

Rationale for Targeting the PI3K/mTOR Pathway

The PI3K/mTOR pathway is one of the most frequently altered signaling networks in human cancers, with mutations or amplifications occurring in approximately 30-50% of tumors. Common genetic alterations include PIK3CA mutations, PTEN loss, and Akt amplifications. These changes lead to constitutive pathway activation, promoting tumor growth, survival, and resistance to therapy. Consequently, targeting this pathway has emerged as a promising therapeutic strategy in oncology.

Current Classes of PI3K/mTOR Pathway Inhibitors

PI3K Inhibitors

PI3K inhibitors can be classified based on their specificity: pan-PI3K inhibitors (targeting all class I isoforms), isoform-selective inhibitors, and dual PI3K/mTOR inhibitors. Examples include idelalisib (PI3Kδ inhibitor approved for hematologic malignancies), alpelisib (PI3Kα inhibitor approved for breast cancer), and copanlisib (pan-PI3K inhibitor).

mTOR Inhibitors

mTOR inhibitors are divided into rapalogs (allosteric inhibitors of mTORC1, such as everolimus and temsirolimus) and ATP-competitive inhibitors that target both mTORC1 and mTORC2 (e.g., sapanisertib and vistusertib). The latter category shows broader pathway inhibition and potentially greater antitumor activity.

Dual PI3K/mTOR Inhibitors

These agents (e.g., dactolisib, gedatolisib) simultaneously target both PI3K and mTOR, potentially overcoming resistance mechanisms associated with single-pathway inhibition. However, they often have greater toxicity profiles due to broader pathway suppression.

Therapeutic Applications in Oncology

PI3K/mTOR inhibitors have shown clinical benefit in several cancer types:

• Breast cancer: Alpelisib is FDA-approved for PIK3CA-mutated, hormone receptor-positive, HER2-negative advanced breast cancer in combination with fulvestrant.
• Renal cell carcinoma: Temsirolimus and everolimus are approved for advanced renal cell carcinoma.
• Lymphoma: Idelalisib is approved for relapsed chronic