Purpose: Chemo-resistance in small cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSCs). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. The current study explored the role of the voltage-dependent calcium channel α21 subunit as a CSC marker in chemo-resistant SCLC, and explored the potential mechanisms of α21-mediated chemo-resistance and strategies of overcoming the resistance. Experimental design: α21 positive cells were identified and isolated from SCLC cell lines and patient derived xenografts (PDXs) models, and CSC-like properties were subsequently verified. Transcriptome sequencing and Western Blotting were carried out to identify pathways involved in α21-mediated chemo-resistance in SCLC. Additionally, possible interventions to overcome a21 mediated chemo-resistance were examined. Results: Different proportions of α21+ cells were identified in SCLC cell lines and PDX models. a21 positive 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 chemo-resistance. Activation and over-expression of Erk in the a21 positive H1048 cell line was identified at the protein level. 1B50-1 mAb 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 chemo-resistance. Erk may play a key role in α21 mediated chemo-resistance. 1B50-1 inhibitors may serve as potential anti-SCLC drugs.
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