Mechanistic Exploration Of Cancer Stem Cell Marker Voltage-Dependent Calcium Channel Alpha 2 Delta 1 Subunit-Mediated Chemotherapy Resistance In Small-Cell Lung Cancer

Purpose: Chemoresistance in small-cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSC). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. This study explored the role of the voltage-dependent calcium channel alpha 2 delta 1 subunit as a CSC marker in chemoresistance of SCLC, and explored the potential mechanisms of alpha 2 delta 1-mediated chemoresistance and strategies of overcoming the resistance.Experimental Design: alpha 2 delta 11-positive cells were identified and isolated from SCLC cell lines and patient-derived xenograft (PDX) models, and CSC-like properties were subsequently verified. Transcriptome sequencing and Western blotting were carried out to identify pathways involved in alpha 2 delta 1-mediated chemoresistance in SCLC. In addition, possible interventions to overcome alpha 2 delta 1-mediated chemoresistance were examined.Results: Different proportions of alpha 2 delta 1 cells were identified in SCLC cell lines and PDX models. alpha 2 delta 1 cells exhibited CSC-like properties (self-renewal, tumorigenic, differentiation potential, and high expression of genes related to CSCs and drug resistance). Chemotherapy induced the enrichment of alpha 2 delta 1(+) cells instead of CD133(+) cells in PDXs, and an increased proportion of alpha 2 delta 1(+) cells corresponded to increased chemoresistance. Activation and overexpression of ERK in the alpha 2 delta 1-positive H1048 cell line was identified at the protein level. mAb 1B50-1 was observed to improve the efficacy of chemotherapy and delay relapse as maintenance therapy in PDX models.Conclusions: SCLC cells expressing alpha 2 delta 1 demonstrated CSC-like properties, and may contribute to chemoresistance. ERK may play a key role in alpha 2 delta 1-mediated chemoresistance. mAb 1B50-1 may serve as a potential anti-SCLC drug. (C) 2018 AACR.