Neuropilin-2b facilitates resistance to tyrosine kinase inhibitors in non–small cell lung cancer

Dimou, Anastasios; Nasarre, Cécile; Peterson, Yuri K.; Pagano, Rose; Göõz, Monika; Nasarre, Patrick; Drabkin, Harry A.; Armeson, Kent; Gibney, Barry C.; Gemmill, Robert M.; Denlinger, Chadrick E.

doi:10.1016/j.jtcvs.2020.03.166

Cited by 7 publications

(10 citation statements)

References 28 publications

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“…Whereas signaling of NRP1 and NRP2a is regulated by a carboxyl terminal PDZ binding motif and its association with PDZ-domain factors such as GIPC (RGS-GAIP-interacting protein), the cytoplasmic domain of NRP2b interacts with GS3Kβ mediating independent pathways ( 6 , 7 ). Recently, we demonstrated in lung cancer cells that the pro-tumorigenic activity of NRP2 resides primarily in the NRP2b isoform, which is upregulated during TGFβ-induced epithelial-mesenchymal transition (EMT) and is associated with more advanced stage, increased metastasis, and resistance to tyrosine kinase inhibitors ( 8 , 9 ). Mechanistically, signaling to Akt was promoted by NRP2b via recruitment of RTKs and GSK3β, a known PTEN inhibitor, whereas Akt was inhibited by NRP2a via recruitment of PTEN to rapidly extinguish Akt activity ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Isoforms of Neuropilin-2 Denote Unique Tumor-Associated Macrophages in Breast Cancer

Dhupar¹,

Jones²,

Powers³

et al. 2022

Front. Immunol.

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Tumor-associated macrophages (TAMs) exert profound influence over breast cancer progression, promoting immunosuppression, angiogenesis, and metastasis. Neuropilin-2 (NRP2), consisting of the NRP2a and NRP2b isoforms, is a co-receptor for heparin-binding growth factors including VEGF-C and Class 3 Semaphorins. Selective upregulation in response to environmental stimuli and independent signaling pathways endow the NRP2 isoforms with unique functionality, with NRP2b promoting increased Akt signaling via receptor tyrosine kinases including VEGFRs, MET, and PDGFR. Although NRP2 has been shown to regulate macrophage/TAM biology, the role of the individual NRP2a/NRP2b isoforms in TAMs has yet to be evaluated. Using transcriptional profiling and spectral flow cytometry, we show that NRP2 isoform expression was significantly higher in TAMs from murine mammary tumors. NRP2a/NRP2b levels in human breast cancer metastasis were dependent upon the anatomic location of the tumor and significantly correlated with TAM infiltration in both primary and metastatic breast cancers. We define distinct phenotypes of NRP2 isoform-expressing TAMs in mouse models of breast cancer and within malignant pleural effusions from breast cancer patients which were exclusive of neuropilin-1 expression. Genetic depletion of either NRP2 isoform in macrophages resulted in a dramatic reduction of LPS-induced IL-10 production, defects in phagosomal processing of apoptotic breast cancer cells, and increase in cancer cell migration following co-culture. By contrast, depletion of NRP2b, but not NRP2a, inhibited production of IL-6. These results suggest that NRP2 isoforms regulate both shared and unique functionality in macrophages and are associated with distinct TAM subsets in breast cancer.

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Section: Introductionmentioning

confidence: 99%

Isoforms of Neuropilin-2 Denote Unique Tumor-Associated Macrophages in Breast Cancer

Dhupar¹,

Jones²,

Powers³

et al. 2022

Front. Immunol.

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“…Better understanding of the development of this resistance is a significant unmet need in lung adenocarcinoma treatment. The group at Medical University of South Carolina in the present study 1 has identified a mechanism for resistance in EGFR mutant lung adenocarcinoma that relies on the NRP2B-GSK3B-PTEN-AKT axis. This group has previously demonstrated that NPR2B is absent from normal lung tissue and upregulated in lung cancer and that its presence correlates with poor clinical outcomes.…”

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confidence: 93%

“…Observations that activating mutations in the epidermal growth factor receptor (EGFR) gene confer sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib ushered in the modern era of targeted therapy for non-small cell lung cancer (NSCLC). 1,2 EGFR mutations occur in approximately 20% of NSCLC, typically in female patients, nonsmokers, and patients with adenocarcinomas. 3 Despite impressive initial responses, virtually all patients develop resistance to EGFR-TKI due to secondary mutations in EGFR, mutations that activate survival signaling pathways such as MET, evolution of a small cell lung cancer phenotype, or epithelial-tomesenchymal transition (EMT).…”

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confidence: 99%

Commentary: New players in epidermal growth factor receptor tyrosine kinase inhibitor resistance

Sienicki

Onaitis

2021

The Journal of Thoracic and Cardiovascular Surgery

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confidence: 99%

“…In this issue of the Journal, Dimou and colleagues 5 examined the role of Neuropilin-2b (NRP2b) in acquired resistance to EGFR-TKI in NSCLC. Previous studies by this group 6,7 had demonstrated that EMT induced in NSCLC cells by transforming growth factor beta (TGF-b) coincides with up-regulation of NRP2b, and that NRP2b is essential for TGF-b-mediated lung cancer progression and metastasis.…”

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confidence: 99%

Commentary: Keeping the target painted for precision cancer therapy

Schrump

Hoang

2021

The Journal of Thoracic and Cardiovascular Surgery

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Identification and Sequencing Trial) trial only uses the first-generation TKI erlotinib in EGFR-mutant patients. Finally, at present, immunotherapy approaches are not effective in patients with EGFR mutations. Whether programmed cell death protein 1/programmed death-ligand 1 expression and tumor mutational burden are increased when NR2B is upregulated will be an interesting question.In summary, this is a very interesting study that presents a novel resistance mechanism of EGFR TKI resistance. Elegant signal transduction experiments are described that may eventually lead to therapeutic advances. Surgeons must be involved in and aware of this type of research so that we can develop new therapies for these patients and communicate effectively with oncologists and patients.

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Neuropilin-2b facilitates resistance to tyrosine kinase inhibitors in non–small cell lung cancer

Cited by 7 publications

References 28 publications

Isoforms of Neuropilin-2 Denote Unique Tumor-Associated Macrophages in Breast Cancer

Isoforms of Neuropilin-2 Denote Unique Tumor-Associated Macrophages in Breast Cancer

Commentary: New players in epidermal growth factor receptor tyrosine kinase inhibitor resistance

Commentary: Keeping the target painted for precision cancer therapy

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