We discovered that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), which was usually found in nerve cells throughout the brain, was widely shown in mesenchymal non-small cell lung cancers (NSCLC) and their exosomes and was partly responsible for promoting NSCLC invasion and metastasis. However, little is known about the biologic function of UCHL1 and its therapeutic potential in high-grade neuroendocrine lung cancers (HGNEC) including small cell lung cancer (SCLC) and large cell neuroendocrine cancer (LCNEC). Despite a high overall mutation rate in HGNEC, there are currently no molecularly targeted agents with proven clinical benefit for this disease. Here we show preclinical efficacy evoked by targeting UCHL1 that was relevant to prognosis in HGNEC.
We assessed the protein expressions of UCHL1 in SCLC cell lines (H69, H82, H526) and NSCLC cell lines, additive chemotherapeutic effects by using the combination of cisplatin/etoposide (PE) or cisplatin/irinotecan (PI) with selective UCHL1 inhibitors (WP1130 and LDN57444), whether the immunohistochemical (IHC) expression level of UCHL1 was associated with prognosis and recurrence in HGNEC patients, and the detectability of UCHL1 mRNA by circulating extracellular vesicles (EVs) in lung cancer patients.
UCHL1 was overexpressed in all the SCLC cell lines and mesenchymal NSCLCs but not an epithelial NSCLC cell line. In SCLC model in vitro, combined the target of UCHL1 by selective UCHL1 inhibitors significantly improved the response of PE and PI therapies. IHC analysis of 72 HGNEC patient’s tumor samples (SCLC/ LCNEC = 34/38) demonstrated that UCHL1 expression significantly correlated with unfavorable overall and recurrence-free survival and contributed to distinguishing SCLC from LCNEC. EVs isolated from lung cancer cell lines and the serum from SCLC and adenocarcinoma patient were verified by electron microscopy and nanoparticle tracking analysis. Increased EVs-derived UCHL1 level was shown in the serum from 2 out of 5 SCLC patients with immunohistochemically high UCHL1 expression while no expression was observed in that from 5 adenocarcinoma patients.
UCHL1 can be a potential prognostic marker and a promising druggable target in HGNEC.
Clinical trial identification
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All authors have declared no conflicts of interest.