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

PI3K-Akt Signaling Pathway in Cancer Treatment

The PI3K-Akt pathway represents a critical therapeutic target in cancer treatment, with FDA-approved AKT inhibitors like capivasertib demonstrating significant clinical benefit in PIK3CA/AKT1/PTEN-altered breast cancers, and emerging evidence supporting pathway inhibition across multiple cancer types including hepatocellular carcinoma, brain metastases, and hematologic malignancies. 1

Pathway Mechanism and Cancer Biology

The PI3K/Akt/mTOR pathway functions as a kinase cascade controlling cellular proliferation and apoptosis, closely linked to cell cycle regulation 2. The mechanism operates through:

• PI3K activation occurs via cell surface growth factor receptor binding, triggering formation of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which subsequently activates Akt and multiple downstream cellular events including mTOR 2
• AKT activation in tumors results from upstream signaling pathway activation, AKT1 mutations, loss of PTEN function, or PIK3CA mutations 1
• Pathway dysregulation is upregulated in subsets of hepatocellular carcinoma patients and frequently activated in brain metastases across multiple cancer types 2

FDA-Approved Targeted Therapy

Capivasertib (TRUQAP) with fulvestrant is FDA-approved for HR-positive, HER2-negative breast cancer with PIK3CA/AKT1/PTEN alterations after progression on aromatase inhibitor-based treatment. 1

Clinical Efficacy Data

The CAPItello-291 trial demonstrated compelling outcomes in PIK3CA/AKT1/PTEN-altered tumors 1:

• Progression-free survival: 7.3 months vs 3.1 months (HR 0.50,95% CI 0.38-0.65, p<0.0001) 1
• Objective response rate: 26% vs 8% in patients with measurable disease 1
• Median duration of response: 10.2 months vs 8.6 months 1

Mechanism of Action

Capivasertib inhibits all three AKT isoforms (AKT1, AKT2, AKT3) and blocks phosphorylation of downstream AKT substrates 1. In preclinical models, capivasertib reduced growth of breast cancer cell lines with PIK3CA/AKT1 mutations or PTEN alterations, and inhibited tumor growth in estrogen receptor-positive breast cancer xenografts with these alterations 1.

Cancer-Specific Applications

Hepatocellular Carcinoma

mTOR inhibitors like rapamycin showed promising results in HCC cell lines, though clinical trial data in HCC patients was not available at the time of consensus guidelines. 2

The pathway is upregulated in HCC subsets, representing a rational therapeutic target alongside MAPK pathway inhibition and growth factor receptor targeting 2.

Brain Metastases

PI3K-AKT pathway activation is consistently elevated in brain metastases compared to extracranial sites across melanoma, breast, lung, and kidney cancers, with OXPHOS and PHGDH inhibitors showing enhanced anti-tumor activity specifically against brain metastases. 2

Key findings include:

• Melanoma brain metastases: PTEN loss predicts increased brain metastasis risk, and PI3K-AKT activation is required for early brain colonization 2
• Whole exome sequencing: Identified new PI3K-AKT pathway mutations in 40-50% of brain metastases across primary cancer types 2
• Metabolic reprogramming: Brain metastases demonstrate increased OXPHOS metabolism and decreased immune infiltration compared to extracranial metastases 2
• Therapeutic resistance: Increased PI3K-AKT activation, elevated OXPHOS, and decreased immune infiltration correlate with resistance to BRAF/MEK inhibitors and anti-PD-1 immunotherapy 2

Ischemic Stroke Neuroprotection

The PI3K-Akt signaling axis functions as an endogenous protector that can prevent apoptotic pathway activation during cerebral ischemia 2. The pathway:

• Enhances neuronal survival as a major downstream cascade of neurotrophic factors (NGF, IGF-1, BDNF) 2
• Regulates survival genes including Bcl-XL and inhibitor-of-apoptosis proteins through CREB and NF-κB transcription factors 2
• Directly inhibits apoptosis via Akt phosphorylation of FOXOs (blocking death gene expression) and BAD (repressing BAD-induced apoptosis) 2
• Represents a therapeutic target for neuroprotective drug development in cerebral ischemic stroke 2

Biomarker-Guided Treatment Selection

PTEN loss strongly predicts response to AKT pathway inhibitors, and pathway activation markers (phospho-AKT, phospho-S6K) should guide therapy selection. 3

Molecular Testing Requirements

• FoundationOne CDx next-generation sequencing identifies eligible PIK3CA/AKT1 activating mutations or PTEN loss-of-function alterations in FFPE tumor specimens 1
• Receptor status changes can occur between extracranial and intracranial sites in breast cancer, with 20.8% estrogen-receptor discordance in brain metastases 2
• Tissue acquisition challenges in brain metastases may be addressed through circulating tumor DNA analysis, though brain-derived plasma ctDNA levels can be low 2

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

The rationale for combination approaches includes:

• Multiple pathway entry points exist for inhibition in cancers like colorectal carcinoma 3
• Enhanced efficacy demonstrated with AKT inhibitors (Perifosine) and PI3K inhibitors (PI103) in colorectal cancer models 3
• Particular promise in breast cancers with PI3K mutations when combining with endocrine therapy 3, 1

Clinical Implementation Considerations

Safety Monitoring

Capivasertib requires specific monitoring due to exposure-response relationships for toxicities 1:

• Diarrhea, rash, and hyperglycemia show dose-dependent increases (CTCAE Grade 2-4) 1
• Geriatric patients (≥65 years) experience higher rates of Grade 3-5 adverse reactions (57% vs 36%), dose reductions (30% vs 15%), and discontinuations (23% vs 8%) compared to younger patients 1
• Hepatic impairment: Monitor patients with moderate hepatic impairment for adverse reactions due to potential increased exposure 1

Dosing Considerations

• Standard regimen: 400 mg orally twice daily for 4 days followed by 3 days off treatment each week 1
• No dose adjustment required for mild-moderate renal impairment (CLcr 30-89 mL/min) or mild hepatic impairment 1
• Food effects: No clinically meaningful differences with high-fat or low-fat meals 1

Resistance Mechanisms and Future Directions

The PDK1-mTORC2-SGK axis can substitute for AKT in survival signaling and represents a major resistance mechanism to PI3K and AKT inhibitors. 4

Additional AKT-independent signaling branches include:

• Rac signaling mediates actin cytoskeleton reorganization regulating cancer cell migration, invasion, and metabolism 4
• TEC family kinase BTK plays critical roles in B cell malignancy and represents an effective therapeutic target 4
• Multiple PIP3-dependent signaling proteins critically contribute to cancer progression beyond AKT 4

Understanding these AKT-independent mechanisms is crucial for developing more effective PI3K pathway targeting strategies 4.