Abstract
Small cell lung cancer (SCLC) is a high-grade malignancy, and treatment strategies have not changed for decades. In this study, we searched for novel targets for antibody-drug conjugate (ADC) therapy for SCLC. We 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 (NRXN1). The cell surface overexpression of NRXN1 was confirmed using flow cytometry in SCLC cell lines (SHP77 and NCI-H526). 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.
Highlights
Small cell lung cancer (SCLC) accounts for 10–15% of lung cancer, and its prognosis has remained relatively dismal for years [1]
Since Rudin et al reported a new model of SCLC subtypes based on the expressions of four key transcription regulators (ASCL1, NeuroD1, Yes-associated protein 1 (YAP1), and POU class 2 homeobox 3 (POU2F3)) [11], we compared the results of our clustering analysis with their subtypes (Supplementary Figure 1)
We identified 31 membrane proteins as candidates for novel antibody-drug conjugate (ADC) targets and demonstrated that NRXN1 is a promising target for ADCs in SCLC
Summary
Small cell lung cancer (SCLC) accounts for 10–15% of lung cancer, and its prognosis has remained relatively dismal for years [1]. Conventional platinum-based chemotherapy regimens with or without radiation remain the standard first-line treatment for SCLC. Atezolizumab was approved for use in combination with carboplatin and etoposide as a first-line treatment for adult patients with extensive-stage SCLC, the median overall survival period, compared with that for chemotherapy alone, was only prolonged for a few months [3]. The role of surgery has been limited to rare (less than 5% of patients) for early-stage disease [4]. SCLC is more responsive to initial cytotoxic chemotherapy than non-small cell lung cancer, most patients relapse with a relatively resistant disease
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
