Expression Patterns of DLL3 across Neuroendocrine and Non-neuroendocrine Neoplasms Reveal Broad Opportunities for Therapeutic Targeting

Abstract

Abstract: Neuroendocrine neoplasms (NEN) encompass a diverse set of malignancies with limited precision therapy options. Recently, therapies targeting DLL3 have shown clinical efficacy in aggressive NENs, including small cell lung cancers and neuroendocrine prostate cancers. Given the continued development and expansion of DLL3-targeted therapies, we sought to characterize the expression of DLL3 and identify its clinical and molecular correlates across diverse neuroendocrine and non-neuroendocrine cancers. Here, we interrogated paired DNA and RNA-sequencing from 1,589 NENs across 29 sites, as well as 203,252 tumors across 47 cancer types. We found that high transcriptomic levels of DLL3 correlated with more aggressive histologic and mutational patterns in NENs, with adverse survival outcomes being reflected in NENs originating from the lung, pancreas, stomach, and small bowel. The heterogeneity in DLL3 expression across NENs was largely explained by site of origin, with lung, prostate, and bladder NENs exhibiting relatively high levels of DLL3, whereas gastroenteropancreatic NENs displayed relatively low expression levels. Although the therapeutic targeting of DLL3 may be less applicable for gastroenteropancreatic NENs, we did find an upregulation of alternative targets such as SEZ6, CELSR3, and SSTR2 in these settings. Lastly, expanding our investigation into non-neuroendocrine cancers, we detected an enrichment of DLL3 in both low-grade and high-grade gliomas, Merkel cell carcinomas, medulloblastomas, and melanomas, with such enrichment being associated with prolonged overall survival in gliomas, but worse overall survival in melanomas. Altogether, we demonstrate that DLL3 represents an attractive target for subsets of neuroendocrine and non-neuroendocrine cancers and uncover opportunities for future therapeutic strategies.

Significance: DLL3-targeted therapies have recently shown robust clinical efficacy in aggressive neuroendocrine cancers, positioning them to fulfill a great unmet need in these settings. Here, we examine the clinical and biological correlates of DLL3 expression in both neuroendocrine and non-neuroendocrine cancers. Our findings may stimulate the development and application of DLL3-targeted therapies, as well as other precision therapies, in neuroendocrine cancers and beyond.

Figure 1

Expression patterns of DLL3 across NENs. A, Violin plots displaying expression of DLL3 in NENs and ADCs originating from the lung or prostate. B, Violin plots displaying expression of DLL3 in lung NENs by histologic grade. Bar plots above show proportion of histologic grade that was defined as DLL3-high. LNEC, large cell neuroendocrine carcinoma; SNEC, small cell neuroendocrine carcinoma. C, Differences in genetic alterations between DLL3-high and -low NENs, as well as breakdown of samples with concurrent mutations or wildtype status in TP53 and RB1 by DLL3-high or -low NENs. D, Circular bar plot displaying proportion of DLL3-high samples by NEN anatomic site with sample sizes shown in parentheses. Bar color represents median DLL3 expression for the site. E, Heatmap displaying relative expression of DLL3, ASCL1, and NEUROD1 in DLL3-high and -low NENs from the lung, prostate, bladder, stomach, pancreas, and small bowel. F, Forest plot showing association between DLL3 expression level and real-world overall survival. Dotted line represents the hazard ratio of 1.0. *, q < 0.05; **, q < 0.01; ***, q < 0.001.

Figure 2

Correlates of DLL3 expression with immune repertoire, alternative targets, and non-neuroendocrine cancers. A, Radar plots displaying differences in immune infiltrates between DLL3-high and -low NENs. B, Ridgeline plots comparing the expression density of DLL3 and alternative precision targets in NENs and site-matched ADCs. C, Violin plots, bar plots, and heatmap displaying expression of DLL3, percent DLL3-high, and hazard ratio, respectively, across 47 cancer types. Dotted line depicts threshold for DLL3-high status. *, P < 0.05; **, P < 0.01; ***, P < 0.001.