What is the role of the PI3K (Phosphatidylinositol 3-kinase)-Akt signaling pathway in cancer treatment?

PI3K-Akt Signaling Pathway in Cancer Treatment

Overview of the Pathway

The PI3K-Akt signaling pathway is a critical therapeutic target in cancer treatment, functioning as a kinase cascade that regulates cellular proliferation, apoptosis, and survival, with pathway dysregulation firmly established as a major determinant of cancer cell growth across multiple malignancies. 1

The pathway operates through a specific molecular mechanism: 1

• PI3K associates with cell surface growth factor receptors
• Upon ligand binding, PI3K triggers formation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3)
• PIP3 activates Akt, leading to downstream cellular events
• mTOR represents one of the key downstream targets of Akt activation
• The pathway is closely linked to cell cycle regulation

Clinical Significance Across Cancer Types

Hepatocellular Carcinoma (HCC)

The PI3K/Akt/mTOR pathway is upregulated in a subset of HCC patients and represents a rational therapeutic target. 1

• Molecular targeted therapy such as rapamycin (a naturally occurring mTOR inhibitor) showed promising results in HCC cell lines 1
• However, as of 2010, no published clinical trial results of mTOR-targeting agents in HCC patients were available 1

Brain Metastases

The PI3K-AKT pathway shows increased activation in brain metastases compared to extracranial sites across multiple primary cancer types, making it a particularly important therapeutic target for intracranial disease. 1

Melanoma Brain Metastases

• Increased expression of PI3K-AKT pathway activation markers occurs in all melanoma brain metastases compared to extracranial sites 1
• PTEN loss (which activates the PI3K-AKT pathway) predicts increased risk of brain metastasis in stage III melanoma patients 1
• PI3K-AKT pathway activation is required for early colonization of the brain by melanoma cells 1

Multiple Cancer Types

• Whole exome sequencing identified new mutations in the PI3K-AKT pathway in 40-50% of brain metastases across primary sites 1
• Brain metastases from breast, lung, and kidney cancer show increased PI3K-AKT activation compared to patient-matched non-CNS tumors 1
• Increased PI3K-AKT pathway activation, along with increased OXPHOS metabolism and decreased immune infiltration, correlates with decreased responsiveness to BRAF/MEK inhibitors and anti-PD-1 immunotherapy 1

Therapeutic Approaches

FDA-Approved PI3K Inhibitors

Alpelisib (VIJOICE) is an FDA-approved PI3K inhibitor with predominant activity against PI3Kα, specifically targeting gain-of-function mutations in PIK3CA. 2

Key pharmacological properties: 2

• Mechanism: Inhibits phosphatidylinositol-3-kinase (PI3K) with inhibitory activity predominantly against PI3Kα
• Approved indication: PIK3CA-related overgrowth spectrum (PROS) disorders
• Dosing: Available as 50 mg, 125 mg, and 200 mg tablets, and 50 mg oral granules
• Food effect: Should be taken with a low-fat meal; increases AUC by 77% and Cmax by 145%
• Metabolism: Primarily metabolized by chemical and enzymatic hydrolysis, followed by CYP3A4-mediated hydroxylation

Targeting Strategy Based on Cancer Type

For hepatocellular carcinoma, mTOR inhibitors (downstream of Akt) represent the primary PI3K pathway-targeting approach, though clinical validation remains limited. 1

For brain metastases, PI3K-AKT inhibitors show enhanced anti-tumor activity against intracranial disease compared to extracranial metastases, particularly when combined with OXPHOS or PHGDH inhibitors. 1, 3

For colorectal cancer, both AKT inhibitors (Perifosine) and PI3K inhibitors (PI103) have demonstrated efficacy in preclinical models. 3

For breast cancer, AKT inhibitors show particular promise in HER2-positive and triple-negative subtypes, especially those with PI3K mutations. 3

Combination Therapy Strategies

Combining AKT inhibitors with MEK/ERK inhibitors blocks compensatory pathway activation and is particularly effective in KRAS or BRAF mutant tumors. 3

This combination approach addresses: 1, 3

• The resistance mechanisms that develop with single-agent PI3K/AKT inhibition
• Compensatory pathway activation that limits efficacy of monotherapy
• Enhanced activity in tumors with concurrent pathway dysregulation

Biomarker-Guided Treatment Selection

PTEN loss strongly predicts response to AKT pathway inhibitors and should guide therapy selection. 1, 3

Additional biomarkers for treatment selection: 3

• Pathway activation markers (phospho-AKT, phospho-S6K) can guide therapy selection
• PIK3CA mutations indicate potential responsiveness to PI3K inhibitors like alpelisib
• Receptor status assessment is critical, as it can change between extracranial and intracranial sites 1

Role in Neuroprotection

The PI3K-Akt signaling axis functions as an endogenous protector in cerebral ischemia, enhancing neuronal survival against stress through neurotrophic factor signaling. 1

Protective mechanisms include: 1

• Regulation of survival genes (Bcl-XL, IAPs) through CREB and NF-κB transcription factors
• Direct phosphorylation of FOXOs to inhibit death gene expression (FasL, Bim)
• Phosphorylation of BAD to repress apoptosis
• The PI3K-Akt signaling cascade represents a potential target for neuroprotective drug development in cerebral ischemic stroke 1

Clinical Development Status

Second-generation PI3K/Akt inhibitors demonstrate improved selectivity and effectiveness compared to first-generation compounds, with multiple agents now in clinical trials. 4, 5, 6

The evolution of inhibitor development: 4, 5

• First-generation inhibitors showed high effectiveness with low IC50 but had toxic side effects and poor pharmacological properties
• Second-generation inhibitors are more selective and effective, utilizing specific chemical moieties to form strong hydrogen bond interactions with PI3K/Akt molecules
• Current clinical development focuses on pathway inhibitors either alone or in combination with other therapies

The most effective treatment strategy involves cascading inhibitors of the PI3K/Akt signaling pathway, either alone or in combination with other therapies, rather than monotherapy approaches. 6, 7