Analysis of DLL3 and ASCL1 in Surgically Resected Small Cell Lung Cancer (HOT1702)

Abstract

Background Delta‐like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova‐T), a DLL3‐targeted antibody‐drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete‐scute homolog‐1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early‐stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis. Materials and Methods We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients. Results Seventy‐seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3‐high expression (≥75%) was observed in 44 samples (47%). Sixty‐one (64%) of 95 samples were positive for ASCL1 (expression in ≥5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 was more prevalent in patients with advanced clinical disease. Conclusion DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC. Implications for Practice This article examines the relationship between delta‐like protein 3 (DLL3) and achaete‐scute homolog‐1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova‐T), a DLL3‐targeted antibody‐drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early‐stage SCLC, including with Rova‐T.

Integrated Immunohistochemical Study on Small-Cell Carcinoma of the Lung Focusing on Transcription and Co-Transcription Factors

“…The positive expression rates of ASCL1 and NEUROD1 in our SCLC samples were similar to those found in previous reports [22,27]. The expression of the target molecules in the ASCL1-positive group was consistent with previous findings [31,[33][34][35][36][37][38][39][40][41][42]. As half of the candidate ASCL1-target molecules selected from the gene expression omnibus dataset showed significance in the IHC study of the ASCL1-positive samples, IHC could be a useful method for detecting candidate target molecules for the four key molecules.…”

<p>The Role of DLLs in Cancer: A Novel Therapeutic Target</p>

“…26 In high-grade neuroendocrine lung tumors (including small cell lung cancer (SCLC) and large-cell neuroendocrine cancer (LCNEC)), DLL3 is overactive at the tumor cell surface and positively correlates with achaete-scute homolog-1 (ASCL1), a member of the BHLH family of transcription factors that is involved in neuroendocrine cell fate decisions. [27][28][29] ASCL1 activates DLL3 by binding to special E-box sites in the DLL3 promoter, as observed in the dorsal neural tube. 30 In a recent study, LCNEC was divided into two molecular phenotypes based on the expression of DLL3 and ASCL1.…”

“…56 In GI-NEC, SCLC and SCBC, DLL3 shows a cytoplasmic distribution in tumor cells (reported as Golgi apparatus-localized in a single SCLC study 114 ) but how this influences Notch signaling is unknown. 27,28,112,113,[115][116][117] In LLC cells, DLL3 localizes to the cell nuclei, inhibiting Notch signaling at the transcriptional level. Akt signaling is activated by DLL3, which promotes LLC cell survival and reduces cell apoptosis.…”

Potential prognostic value of delta-like protein 3 in small cell lung cancer: a meta-analysis

“…Finally, we were left with 16 eligible studies after screening the full text, among which 6 articles were included in our final analysis ( Fig. 1) [20][21][22][23][24][25]. Ten articles were excluded for the following reasons: seven articles were review researches and commentaries, one article did not report hazard ratios and Kaplan-Meier curves and 2 articles were abstracts and did not report relevant outcomes.…”

“…One interpretation of this result was that DLL3 expression varies between different populations. The American study indicated that the high expression of DLL3 was a marker of good prognosis [21], and there was no significant correlation between DLL3 expression and prognosis in several Japan studies [22,25], while the high expression of DLL3 is a marker of poor prognosis in China studies [20,23]. These results showed that the expression of DLL3 might be different in different populations.…”