Together, our findings revealed shared molecular features across MPN and AML, identified a prognostic gene signature for risk stratification, and provided rationale for PI3K/mTOR inhibition as a promising therapeutic strategy in myeloid malignancies.

Co-inhibition of mTOR or the SLC3A2/SLC7A5 complex using dactolisib or JPH203 restores sensitivity to KRAS inhibitors in vitro and in vivo. These findings support combinatorial targeting of mTOR signaling or amino acid transport to overcome intrinsic resistance in KRAS-mutant lung cancer.

P3, N=701, Active, not recruiting, Celcuity Inc | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2025 --> Jun 2026

Treatment with the PI3K inhibitor LY294002 produced changes consistent with those observed upon YBX1 silencing. In a subcutaneous xenograft mouse model, YBX1 silencing was associated with reduced tumor growth and ferroptosis-related changes, effects that were partially reversed by EGF treatment. These findings suggest that YBX1 is associated with ferroptosis-related changes and altered proliferation and migration in A549 cells, potentially involving PI3K/AKT/mTOR signaling, highlighting YBX1 as a potential therapeutic target.

The expression of MYBL2 and CENPF in lung adenocarcinoma increases with LUAD progression. MYBL2 regulates the expression of CENPF in LUAD, and the elevated CENPF promotes the proliferation and migration of LUAD cells. Both MYBL2 and CENPF regulate the proliferation and migration of LUAD through AKT pathway activation.

Mechanistically, FFAs were found to trigger Akt activation, and pharmacological inhibition of this protein by BEZ235 could successfully counteract their cancer-promoting effects. Collectively, these results support the presence of an EV-driven bidirectional interplay between PCa cells and adipocytes, which reprograms the latter toward a lipolytic, tumor-promoting phenotype.

The proteasome inhibitor MG132 confirmed that fisetin accelerates β-catenin and MITF degradation. Additionally, inhibition of the PI3K/AKT pathway by LY294002 or the ERK pathway by PD98059 reversed fisetin's reduction of tyrosinase activity and melanin synthesis, further verifying the participation of these pathways. Computational docking integrated with deep learning-based CNN scoring revealed that fisetin interacts with PKCα, β-catenin, tyrosinase, and TYRP1. Collectively, these findings suggest that fisetin exerts multi-targeted inhibitory effects on melanogenesis, highlighting its potential as a therapeutic and cosmetic agent for hyperpigmentation.

Co-administration of BAY1082439 with siRNA-loaded LNPs also better suppressed tumor growth and reduced liver inflammation in vivo, respectively. These findings establish PIK3CA inhibition as a broadly applicable strategy to boost LNP-mediated RNA interference and highlight the promise of combining functional genomics with nanomaterials to advance RNA-based therapeutics.

P2, N=7, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2025 --> Feb 2027

Critically, the use of a PI3K inhibitor (LY294002) demonstrated that the nicotine-induced downregulation of p53 and upregulation of MMP-2, as well as the enhancement of cellular invasion are dependent on PI3K/AKT pathway activation. These findings conclusively demonstrate that nicotine promotes the malignant transformation of HPV-16 positive cervical cancer cells by altering the expressions of MMP-2, p53, Caspase-3, and p21 via the activation of the PI3K/AKT pathway. This highlights the therapeutic potential of targeting this pathway in cervical cancer treatment.

Interventions utilizing a range of inhibitors at the in vitro level, including the PDGFR-β inhibitor AG1296, the PI3K inhibitor LY294002, the AKT inhibitor MK2206, and the FAK inhibitor Y15, demonstrated that E. multilocularis protoscoleces protein (EmP) induces angiogenesis through PDGFR/PI3K/AKT/FAK signaling pathway. Our findings provide new perspectives on how E. multilocularis infection triggers pathological angiogenesis in the host liver, and may provide a novel anti-angiogenic therapeutic strategy against E. multilocularis infection.

P1, N=12, Terminated, Henan Cancer Hospital | Phase classification: P1/2 --> P1 | Trial completion date: Feb 2025 --> Aug 2025