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Evaluation of the PIK3 pathway in peripheral T-cell lymphoma and NK/T-cell lymphoma
Dachuan Huang1, Tammy Linlin Song1, Maarja-Liisa Nairismägi1
1Lymphoma Genomic Translational Research Laboratory, Division of Cellular & Molecular Research, National Cancer Centre Singapore, Singapore City, Singapore.
Abstract:
Peripheral T-cell lymphomas (PTCL) and natural killer (NK)/T-cell lymphomas (NKTCL) are a heterogeneous group of aggressive malignancies with dismal outcomes and limited treatment options. While the phosphatidylinositol 3-kinase (PIK3) pathway has been shown to be highly activated in many B-cell lymphomas, its therapeutic relevance in PTCL and NKTCL remains unclear. The aim of this study is to investigate the expression of PIK3 and phosphatase and tensin homolog (PTEN) in these subtypes of lymphoma and to identify potential therapeutic targets for clinical testing. Therefore, the expression of PIK3α, PIK3β, PIK3γ, PIK3δ and PTEN was analyzed in 88 cases of PTCL and NKTCL samples by immunohistochemistry. All PTCL and NKTCL samples demonstrated high expression of PIK3 isoforms. In particular, high PIK3α expression was significantly associated with poor survival, even after adjustment for age, International Prognostic Index (IPI) score and anthracycline-based chemotherapy in first line. Notably, copanlisib, a pan-class I inhibitor with predominant activities towards PIK3α and PIK3δ isoforms, effectively inhibited phosphorylation of AKT, 4E-BP-1 and STAT3, causing G0 /G1 cell cycle arrest and resulting in suppression of tumour cell growth in vitro and in vivo. This study provides evidence that targeting the PIK3 pathway, particularly simultaneous inhibition of PIK3α and δ, could be a promising approach for the treatment of PTCL and NKTCL.
Insights
Targeting the phosphatidylinositol 3-kinase (PIK3) pathway shows promise for aggressive lymphomas. High PIK3α expression correlates with poor survival in Peripheral T-cell Lymphoma (PTCL) and Natural Killer/T-cell Lymphoma (NKTCL).
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Peripheral T-cell lymphomas (PTCL) and natural killer (NK)/T-cell lymphomas (NKTCL) are aggressive cancers with poor prognoses.
- The role of the phosphatidylinositol 3-kinase (PIK3) pathway, a key signaling pathway, in PTCL and NKTCL pathogenesis and treatment is not well understood.
- Limited therapeutic options exist for these hematologic malignancies.
Purpose of the Study:
- To investigate the expression levels of PIK3 isoforms and phosphatase and tensin homolog (PTEN) in PTCL and NKTCL.
- To identify potential therapeutic targets within the PIK3 pathway for these lymphoma subtypes.
- To evaluate the efficacy of PIK3 pathway inhibition as a treatment strategy.
Main Methods:
- Immunohistochemistry was used to analyze the expression of PIK3α, PIK3β, PIK3γ, PIK3δ, and PTEN in 88 PTCL and NKTCL patient samples.
- Statistical analysis was performed to correlate PIK3 expression with patient survival, adjusting for established prognostic factors (age, IPI score, first-line chemotherapy).
- In vitro and in vivo experiments assessed the effects of copanlisib, a PIK3 inhibitor, on lymphoma cell growth and signaling pathways (AKT, 4E-BP-1, STAT3).
Main Results:
- All analyzed PTCL and NKTCL samples exhibited high expression of PIK3 isoforms.
- Elevated PIK3α expression was significantly linked to poorer patient survival, independent of clinical prognostic factors.
- Copanlisib effectively inhibited key downstream signaling proteins, induced cell cycle arrest, and suppressed tumor growth in preclinical models.
Conclusions:
- The PIK3 pathway is highly activated in PTCL and NKTCL, suggesting its critical role in these malignancies.
- High PIK3α expression serves as a potential biomarker for poor prognosis in PTCL and NKTCL.
- Targeting the PIK3 pathway, especially with inhibitors like copanlisib that target PIK3α and PIK3δ, represents a promising therapeutic strategy for PTCL and NKTCL.
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