posted on 2023-08-01, 08:42authored byLing Cai, Ralph J. DeBerardinis, Yang Xie, John D. Minna, Guanghua Xiao
<p>Similar and distinct NE score–associated therapeutic sensitivity in SCLC and neuroblastoma cell lines. <b>A,</b> Correlation between NE scores and therapeutic sensitivity for drugs with selected targets. Therapeutic sensitivity data were previously harmonized such that a higher value represents more resistance in each study. For each of the nine selected targets, all compounds with the same target were identified from multiple studies. Pearson correlation coefficient <i>r</i> from correlating compound data with NE scores were calculated for neuroblastoma lines (<i>x</i>-axis values) and SCLC lines (<i>y</i>-axis values), respectively and visualized as a scatter plot, with colors annotating the source of data, and transparency annotating the statistical significance. <b>B,</b> Meta-analysis–summarized correlation between drug therapeutic sensitivity and NE scores in neuroblastoma (<i>x</i>-axis) and SCLC (<i>y</i>-axis) cell lines. Note that high NE scores are associated with resistance to inhibitors of LCK, MEK, XIAP, mTOR, HSP90, and Abl, and sensitivity to BCL inhibitors. NE scores are associated with resistance to BRD inhibitors in neuroblastoma but not SCLC whereas microtubule inhibitors resistance correlates with high NE scores in SCLC but not neuroblastoma cell lines.</p>
Funding
American Cancer Society (ACS)
National Institute of General Medical Sciences (NIGMS)
United States Department of Health and Human Services
Lineage plasticity has long been documented in both small cell lung cancer (SCLC) and neuroblastoma, two clinically distinct neuroendocrine (NE) cancers. In this study, we quantified the NE features of cancer as NE scores and performed a systematic comparison of SCLC and neuroblastoma. We found neuroblastoma and SCLC cell lines have highly similar molecular profiles and shared therapeutic sensitivity. In addition, NE heterogeneity was observed at both the inter- and intra-cell line levels. Surprisingly, we did not find a significant association between NE scores and overall survival in SCLC or neuroblastoma. We described many shared and unique NE score–associated features between SCLC and neuroblastoma, including dysregulation of Myc oncogenes, alterations in protein expression, metabolism, drug resistance, and selective gene dependencies.
Our work establishes a reference for molecular changes and vulnerabilities associated with NE to non-NE transdifferentiation through mutual validation of SCLC and neuroblastoma samples.