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 α21 subunit as a CSC marker in chemoresistance of SCLC, and explored the potential mechanisms of α21-mediated chemoresistance and strategies of overcoming the resistance.

Experimental Design: α21-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 α21-mediated chemoresistance in SCLC. In addition, possible interventions to overcome α21-mediated chemoresistance were examined.

Results: Different proportions of α21⁺ cells were identified in SCLC cell lines and PDX models. α21⁺ 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 α21⁺ cells instead of CD133⁺ cells in PDXs, and an increased proportion of α21⁺ cells corresponded to increased chemoresistance. Activation and overexpression of ERK in the α21-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 α21 demonstrated CSC-like properties, and may contribute to chemoresistance. ERK may play a key role in α21-mediated chemoresistance. mAb 1B50-1 may serve as a potential anti-SCLC drug. Clin Cancer Res; 24(9); 2148–58. ©2018 AACR.

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