Endoplasmic reticulum stress-MMRN1 positive feedback contributes to cisplatin resistance in small cell lung cancer

Background: Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and presents early metastasis and poor prognosis. Chemotherapy with cisplatin (CDDP) remains one of the standards of care in first-line treatment. However, the emergence of acquired resistance to CDDP causes disease progression and cancer recurrence. A comprehensive understanding of the CDDP-resistant mechanisms aids in defining accurate biomarkers and developing potential strategies. Methods: The liquid chromatograph mass spectrometer (LC-MS/MS) was conducted to analyze the differential exosomal proteins from plasma samples of SCLC patients with non-treatment or resistance to CDDP. The online RNA-seq data with clinicopathological information on SCLC patients were downloaded from the Gene Expression Omnibus (GEO) database for further prognostic analysis. The SCLC cell line model of acquired CDDP resistance was established to investigate the role of platelet protein multimerin-1 (MMRN1) in CDDP resistance. Results: MMRN1 was increased in CDDP-resistant SCLC patients and cell line models. Reduction of MMRN1 recovered the sensitivity to CDDP while overexpression of MMRN1 conferred CDDP resistance. The CDDP-resistant SCLC cells disseminated resistant to the CDDP-sensitive SCLC cells via the exosomal MMRN1. Additionally, CDDP treatment induces endoplasmic reticulum (ER) stress and subsequent upregulation of MMRN1. Increasing MMRN1 interacted with binding immunoglobulin protein (BiP) in the ER, maintaining the ER stress in SCLC cells. Conclusions: The present study identified exosomal MMRN1 as a potential biomarker for CDDP resistance in SCLC. MMRN1 sustains ER stress via interaction with BiP and subsequently facilitates CDDP resistance, which might be a promising therapeutic target to overcome CDDP resistance.