NRP1 (Neuropilin 1)

Oncogenic RET gene rearrangements drive a subset of lung adenocarcinomas (LUAD) and the tyrosine kinase inhibitors (TKIs) selpercatinib and pralsetinib are approved therapeutics. By contrast, upfront treatment with selpercatinib and crizotinib in orthotopic tumors yielded complete elimination of 7 of 9 TR.1 tumors and both deepened and prolonged the duration of response in TR.2 tumors. The findings provide new insight into mechanisms of acquired resistance through bypass signaling and highlight the therapeutic benefit of simultaneous upfront blockade of driver oncogenes and dominant resistance mechanisms in LUAD.

We sincerely thank Roesler and Isolan [...].

We read with great interest the recent study by Santana-Bejarano et al [...].

Pharmacologic inhibition of NRP1 or ABL1 reversed ANGPTL4-mediated DDR and HR, and increased HNSCC cell death in combination with cisplatin, in vitro and in vivo. Our results reveal a role for ANGPTL4 in RAD51-dependent DNA repair and suggest that ANGPTL4/NRP1/ABL1/RAD51 may serve as an alternative therapeutic target for HNSCC.

Therapeutically, targeting the TAGLN2 axis synergized with both cisplatin and bevacizumab, potently suppressing tumor progression by impairing neovascularization and promoting vascular normalization. Clinically, exosomal TAGLN2 levels were significantly elevated in GC patient serum. Our study delineates a complete exosome-to-vasculature signaling axis and positions TAGLN2/NRP1/SEMA4D/YAP module as an integrated diagnostic and therapeutic target against metastatic GC.

Future research should focus on translating these findings into clinical applications, including the development of SEMA3B-based epigenetic therapies and combination strategies with anti-angiogenic agents. Key challenges remain in fully delineating the context-dependent dual roles of SEMA3B, understanding its complex interactions within the tumor microenvironment, and overcoming its inactivation mechanisms for effective therapeutic restoration.

Consistently, qPCR analysis in five paired GC and para-carcinoma tissues confirmed higher expression of these genes in tumor samples (p < 0.01). Our findings indicate that hypoxia is a critical determinant of prognosis in GC and is closely associated with an immunosuppressive tumor microenvironment, highlighting its potential value as a prognostic biomarker and therapeutic target.

Additionally, OTUD4 is recruited by NRP1 to deubiquitinate and further stabilize EGFR. These findings enhance our understanding of EGFR signaling in TNBC and may inform novel therapeutic strategies.

Efficacy studies revealed a reduction in mean tumor volume of up to 65% in two independent orthotopic mouse models, with no tumor evident in some of the animals treated with the CCK2p-boundPAPTP construct. Our data suggest that tumor-specific targeting of small molecules may be a promising strategy for precision medicine against PDAC.

On the other hand, NDGA inhibited CBP/p300, decreased H3K27ac levels, and synergized with the EZH2 inhibitor EPZ6438 against PC3 cells. In conclusion, NDGA is a potential epigenetic antineoplastic agent that downregulates EZH2 and H3K27me3 through the NRP1 and PI3K/AKT/mTOR pathways and exerts a synergistic antitumor effect with H3K27ac and EZH2 inhibitors, suggesting that it could be a valuable therapeutic option for prostate cancer.

These findings are highly relevant for clinicians and researchers aiming to enhance ICI effectiveness in solid tumors. Given the ongoing clinical evaluation of iRGD, this simple, non-conjugated strategy offers a feasible and rapidly translatable approach to overcome a key limitation of current ICI therapy and improve outcomes for patients with HCC.