PIK3CD expression

These observations may setup a new crosstalk between tumor inflammatory microenvironment, IL2/JAK3/STAT5 signaling and PI3K/AKT signaling. Targeting PIK3CD may be a promising therapy strategy for GC.

The mainstay of MCL therapies remains the chemo-immunotherapy followed by autologous transplantation but recently several novel therapies have been developed such as BTK inhibitors, Venetoclax, CDK4/6 inhibitors and more recently CAR-T therapies...Finally, the expression of PIK3CD which encodes for a therapeutic target in MCL (such as PI3KDelta inhibitor Idelalisib) was also significantly repressed in UPN-1 as compared to nine other MCL cell lines...This cell line exhibited a major upregulation of E2F1 expression and a down regulation of the cell cycle inhibitor CDKN1A(p21). The potential effects of the direct inhibition of E2F1 using the targeted inhibitor MTA demonstrated a reduction in cell proliferation and induction of apoptosis, suggesting the possibility of associating clinically acceptable E2F1 inhibition strategies to other current therapies.

To further validate this finding, the combination of roginolisib with venetoclax or with another bcl-2 inhibitor S55746 was tested in a broad range of lymphoma cell lines including GRANTA519, JVM2, SP49 (MCL); FARAGE, TMD8 (diffuse large B cell lymphoma); MEC1 (chronic lymphocytic leukemia); MJ (cutaneous T cell lymphoma); and YT (NK lymphoma)...Other BCRi such as idelalisib, duvelisib and acalabrutinib were used at 5 μM concentrations as positive controls...In addition, roginolisib synergized with venetoclax in lymphoma cell lines and CLL patient samples. Our data support extending this combination strategy to clinical trials in hematological malignancies.

Our findings reveal that PIK3CD expression is associated with prognosis, EMT, and tumor immune infiltration in BRCA patients.

In-vitro functional assays have further demonstrated that a combination of Idelalisib and SRPIN340 achieved a synergistic drug effect (with drastically reduced cell viabilities/growths of tumor spheroids) in inhibiting the advanced tumor cells. In summary, our study has suggested a promising potential of utilizing PI3Kδ-S (an oncogenic isoform conferring drug resistance and exempt from PTEN regulation) as a prognostic biomarker and drug target in advanced endocrine cancers.

Material and MethodsWe have used patient derived tumor cells to evaluate roginolisib in combination with immune-targeted or molecularly-targeted therapies to identify synergies that could be translated to future clinical studies.Results and DiscussionsHere, we show that in two ex vivo co-culture models of patient-derived mesothelioma cells with matched PBMC, the addition of roginolisib to cisplatin plus nivolumab specifically increased activated Ki67+/IFNg+ CD8 T cells and M1-like macrophages, and concomitantly decreased Tregs, exhausted TIM3+ CD8 T cells and MDSCs with an overall effect to increase the antitumoral immune response. Our data supports combining roginolisib with checkpoint inhibitors, for example in lung cancers, and targeted molecular therapies such as BCL2 inhibitors in CLL. The mechanistic synergy of these combinations has potential to provide greater patient benefit compared to the use of these medicines as single agents.

Our data demonstrated for the first time the synergistic effect of a novel combination of KPT-330 and CX-4945 on cell growth arrest and apoptosis in AML cells, and identify the underlying mechanism bytargeting the PIK3CD/AKT1/FOXO3 signaling pathway, which highlighted the feasibility of clinical trials for combination therapy of AML patients.

IOA-244 is a first-in-class non-ATP-competitive, PI3Kδ inhibitor with direct antitumor in vitro activity correlated with PI3Kδ expression. The ability to modulate T cells, in vivo antitumor activity in various models with limited toxicity in animal studies provides the rationale for the ongoing trials in patients with solid tumors and hematologic cancers.

Compared with PCa expressing the full-length PI3Kδ-L, PCa expressing PI3Kδ-S exhibits enhanced drug resistance properties, including a higher cell viability, more antiapoptotic and invasive capacities, and constitutively activated PI3K/AKT signaling, in the presence of PI3Kδ/PI3K inhibitors (Idelalisib, Seletalisib, Wortmannin, and Dactolisib). Additionally, SRSF2 has been identified as a critical splicing factor mediating exon 20 skipping in PIK3CD pre-mRNA. The inhibition of the SRSF2 activity by SRPIN340 successfully sensitizes AA PCa cells to PI3Kδ inhibitors, suggesting a novel therapeutic option for Idelalisib-resistant tumors.

Mechanistically, PIK3CD regulates the activity of p21 activated kinase (PPAK3) and plecstrin 2 (PLEK2) through axonogenesis pathway. The findings provide a novel mechanism of PIK3CD-mediated GBM development and suggest PIK3CD might be a target of GBM.

A PD-1 blockade (10 mg/kg) and a PI3Kγδ inhibitor (IPI145; 15 mg/kg) were then administered every other day for 2 weeks... These findings collectively indicate that PI3Kγ and PI3Kδ are clinically relevant targets in an immunosuppressive TME. Combining PI3Kγδ inhibitor, RT, and PD-1 blockade may thus be a viable approach, helping to overcome the therapeutic resistance of immunologically cold tumors such as breast cancer.

MiR-224 plays a key role in the progression of DLBCL, and the proliferation and invasion of HBL1 cells can be suppressed by targeted inhibition of PIK3CD.

Our results suggested that ciRS-7 can interact directly with miR-7, resulting in upregulation of RAF-1/PIK3CD expression and enhancing metastatic progression of OSCC.

Additionally, in MM‑468 cells, the compound downregulated the release of IL‑8 through repressing IL‑8, MAPK1, MAPK3, CCDC88A, STAT3 and PIK3CD gene expression. In conclusion, the data obtained in the present study indicate that the polyphenol compound GOSS may provide a valuable tool in TNBC therapy.

In conclusion, we found that the novel LSCC-related gene DLEU2 enhances the malignant properties of LSCCs via the miR-30c-5p/PIK3CD/Akt axis. DLEU2 and its targeted miR-30c-5p/PIK3CD/Akt axis may represent valuable prognostic biomarkers and therapeutic targets for LSCCs.

Furthermore, TCPA prognostic analysis observed that several of the key molecules of the PI3K/AKT/mTOR signaling pathway &lsqb;PTEN, p-AKT (S473) and p-mTOR (S2448)] were also positively correlated with OS in patients with ccRCC (P < 0.05). In conclusion, the present study suggested that several members of the PI3K/AKT/mTOR signaling pathway, especially PTEN, may be favorable prognostic factors in ccRCC, which indicated that the PI3K/AKT/mTOR signaling pathway may be implicated in ccRCC initiation and progression.

These results indicate that PI3Kδ expression is observed in both the immune cells which are fashioning the suppressive microenvironment and in cancer cells. These findings suggest an approach to identify patients for treatment guided by cell type expression of PI3K isoforms, and provide strategies for duvelisib use as monotherapy and in combinations with PD-1 checkpoint inhibitors and other agents.

Taken together, these findings indicate that in addition to the established effects of duvelisib on malignant B cells and non-malignant immune cells of the TME, duvelisib can also directly inhibit signaling and proliferation of solid tumor cells expressing PI3K-δ and/or PI3K-γ, providing further rationale for clinical investigation of duvelisib for the treatment of solid tumors. Accordingly, the combination of duvelisib with pembrolizumab is currently being evaluated in patients with head and neck squamous cell carcinoma.