PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma)

This review contains 142 citations, 60 of which are detailed examples of this mechanism. Our analysis of the literature shows that TEXs deliver specific ncRNAs to macrophages, reprogramming them toward an M2 phenotype via pathways such as PTEN/PI3Kγ, Wnt/β-catenin, and STAT3. This polarization amplifies immunosuppressive factor secretion and promotes tumor metastasis, chemoresistance, and immune evasion. These insights provide a theoretical foundation for novel TME-targeted therapies, potentially improving outcomes in refractory cancers.

In the syngeneic CT26 model, dual PI3Kδ/γ inhibition (BR101801 or duvelisib), unlike selective PI3Kδ inhibition (idelalisib), synergized with RT (7.5 Gy) to suppress tumor growth and induce durable immune memory. Furthermore, blockade of the IFN-I receptor abolished CD8+ T cell infiltration and M2-like macrophage suppression, abrogating antitumor efficacy and confirming the requirement for IFN-I signaling. These findings identify macrophage-driven activation of the cGAS-STING-IFN-I axis as a key mechanism by which dual PI3Kδ/γ inhibition potentiates RT, providing a strong scientific rationale for its development as an immunomodulatory radiosensitizer.

We further discuss methodological challenges, translational opportunities, and future directions in developing exosome-based diagnostics and miRNA-loaded therapeutic platforms. Understanding exosomal miRNA networks can pave the way for precision detection and targeted therapy in pancreatic cancer.

Additionally, EE dose-dependently inhibited apoptosis and downregulated PI3K/AKT phosphorylation as well as the B-cell lymphoma 2-associated X protein/B-cell lymphoma-2 (Bax/Bcl-2) ratio. These findings suggest that EE alleviates cellular senescence in HSFs mainly via the PI3K/AKT pathway by attenuating oxidative stress and apoptosis, highlighting its potential as a therapeutic agent for anti-aging strategies.

The key frames from the MD simulations were selected using the OWSCA algorithm. Ligand and protein performance were evaluated through RMSD, RMSF, and hydrogen bond analyses, applying cutoff distances of 3.5 Å and 30°.

Further, EGFR inhibitor erlotinib synergized with the RAS(ON) multi-selective inhibitor RMC-7977 in KRASQ61H-mutant PDAC cell lines and in cell lines with highly active EGFR by mitigating ERK rebound activity. KRASi-resistant cell lines featured sustained ERK/MAPK dependence despite decreased ERK activity. Together, these findings enhance the understanding of intrinsic and acquired resistance to KRASi and identify therapeutic vulnerabilities that can potentially be exploited for KRASi combination therapies in pancreatic cancer patients.

The PI3K inhibitors GDC-0032 and INK1117 for PI3K-α and AZD8186 for PI3K-β are now being studied in clinical trials. Research on the clinical development, therapeutic utility, and structural insights of new PI3K inhibitors is the main emphasis of this review. The inhibitors have been shown promising anticancer activity relationships.

Among them, Epirubicin, Doxorubicin, and Daunorubicin; all anthracycline chemotherapy agents; are known to inhibit cancer progression by slowing or halting cell growth. Molecular dynamics simulations further validated the QSAR screening results, confirming that Epirubicin forms the most stable and tightly bound complex with PI3Kγ, with ΔGbind values of -3.81 kcal/mol for PI3Kγ-M192 and -4.47 kcal/mol for PI3Kγ-Epirubicin. These findings indicate that the QSAR model could function as a targeted screening tool, facilitating the identification of drugs with strong affinity for the PI3Kγ receptor, and ultimately improving the hit rate compared to random screening approaches.

In vitro, PIK3CG, CAMK2A, NFKB1, PSMA4, and PSMB1 were upregulated in OC cell lines, and knockdown of PIK3CG notably suppressed the proliferative, migratory, and invasive capabilities of OC cells. The PRG model established in this study may contribute to the assessment of immunotherapeutic response and prognosis for OC patients.

Thus, this study uncovered a mechanism that supports elevated PI3K signaling in PDAC, thereby reducing the need for KRAS to directly activate the PI3K pathway. PTEN inactivation by intramolecular disulfide bond formation and elevated expression of PI3K isoforms in pancreatic cancer leads to unchecked KRAS-independent PI3K signaling, highlighting the need for therapeutic approaches targeting constitutive PI3K signaling.

Transcriptomic profiles of m-TCLs recapitulated human-PTCL-GATA3 transcriptome and distinguished PTCL-NOS subtypes. Preclinical assessment of m-TCLs with PI3Kγ/δ inhibitors significantly improved survival, supporting a therapeutic approach for the p53-aberrant PTCL-GATA3.

These findings establish VEGFA-VEGFR2 signaling by PI3Kγ activation as a key driver of acquired resistance to KRAS G12D inhibition and provide a rationale for combining VEGFA-VEGFR2 inhibition with KRAS blockade in KRAS-mutant cancers. VEGFA-VEGFR2 signaling activation is a common feature of MRTX1133 resistance in KRAS G12D cancer cells Nuclear translocation of SP1 by AKT activation promotes VEGFA transcription in MRTX1133-resistant modelsInteraction of p110γ-p101 with KRAS activates PI3Kγ in the resistant models VEGFA-VEGFR2 inhibition reverses MRTX1133 resistance in vitro and in vivo.