Oncotarget: NRXN1 as a novel potential target for small cell lung cancer

September 30, 2020

The cover for issue 39 of Oncotarget features Figure 4, "Apoptosis assay of NRXN1-targeted ADC at IC50 dose calculated by growth inhibition curves," by Yotsumoto, et al. which reported that the authors identified transmembrane proteins overexpressed specifically in SCLC with little or no expression in normal tissues and decided to focus on the cell adhesion molecule neurexin-1.

The cell surface overexpression of NRXN1 was confirmed using flow cytometry in SCLC cell lines.

The combination of a primary anti-NRXN1 monoclonal antibody and a secondary ADC exhibited anti-tumor activity in SCLC cell lines.

Moreover, the knockout of NRXN1 in SHP77 cells resulted in a loss of the anti-tumor activity of NRXN1-mediated ADC therapy.

Thus, NRXN1 could be a novel target for ADC therapy for the treatment of SCLC that is worth further research.

Dr. Daiya Takai from The University of Tokyo Hospital and Dr. Takuma Yotsumoto from The University of Tokyo Graduate School of Medicine said, "Small cell lung cancer (SCLC) accounts for 10–15% of lung cancer, and its prognosis has remained relatively dismal for years."

Figure 4: Apoptosis assay of NRXN1-targeted ADC at IC50 dose calculated by growth inhibition curves. Late apoptotic cells were quantified by Cy7-conjugated annexin-V and PI using flow cytometry. Results were analyzed using a one-way ANOVA followed by the Dunnett multiple comparisons test (*P< 0.05; **P< 0.01; ***P< 0.0001 versus no-treatment control group; Dunnett test). Error bars represent the SD of the mean. mAb, monoclonal antibody.

Considering the high sensitivity of SCLC to chemotherapy, the selective delivery of a cytotoxic agent using ADC could be a novel treatment strategy for SCLC.

Five ADCs have been approved by The Food and Drug Administration:

  1. Brentuximab vedotin for Hodgkin lymphoma
  2. Ado-trastuzumab emtansine for HER2-positive metastatic breast cancer
  3. Inotuzumab ozogamicin for acute lymphoblastic leukemia
  4. Gemtuzumab ozogamicin for CD33-positive acute myeloid leukemia, and
  5. Trastuzumab deruxtecan for unresectable or metastatic HER2-positive breast cancer patients who have received two or more prior anti-HER2-based regimens in a metastatic setting.
In SCLC, DLL3, a cell surface Notch ligand that appears to be a direct downstream target of ASCL1, has been identified as a novel target for ADCs.

In this study, the Oncotarget authors aimed to identify novel molecular targets for ADCs in SCLC.

In this study, the Oncotarget authors aimed to identify novel molecular targets for ADCs in SCLC.

They herein report that NRXN1-mediated ADC exhibited anti-tumor activity in vitro, and thus NRXN1 could be a novel target of ADCs for SCLC.

The Takai/Yotsumoto Research Team concluded in their OncotargetResearch Paper "we identified NRXN1 as a new target for ADCs by screening membrane proteins using a computational-biological approach. The combination of the primary anti-NRXN1 monoclonal antibody and the secondary ADC exhibited anti-tumor activity in an NRXN1-expression dependent manner. NRXN1 could be a novel potential target of ADCs for SCLC that is worth further research."

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DOI - https://doi.org/10.18632/oncotarget.27718

Full text - https://www.oncotarget.com/article/27718/text/

Correspondence to - Daiya Takai - dtakai-ind@umin.ac.jps and Takuma Yotsumoto - tyotsumoto-ths@umin.ac.jp

Keywords - antibody-drug conjugates, small cell lung cancer, novel molecular targets, NRXN1, cell adhesion molecule

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