Heterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models

Abstract

Molecular subtypes of small cell lung cancer (SCLC) defined by the expression of key transcription regulators have recently been proposed in cell lines and limited number of primary tumors. The clinical and biological implications of neuroendocrine (NE) subtypes in metastatic SCLC, and the extent to which they vary within and between patient tumors and in patient-derived models is not known. We integrate histology, transcriptome, exome, and treatment outcomes of SCLC from a range of metastatic sites, revealing complex intra- and intertumoral heterogeneity of NE differentiation. Transcriptomic analysis confirms previously described subtypes based on ASCL1, NEUROD1, POU2F3, YAP1, and ATOH1 expression, and reveal a clinical subtype with hybrid NE and non-NE phenotypes, marked by chemotherapy-resistance and exceedingly poor outcomes. NE tumors are more likely to have RB1, NOTCH, and chromatin modifier gene mutations, upregulation of DNA damage response genes, and are more likely to respond to replication stress targeted therapies. In contrast, patients preferentially benefited from immunotherapy if their tumors were non-NE. Transcriptional phenotypes strongly skew towards the NE state in patient-derived model systems, an observation that was confirmed in paired patient-matched tumors and xenografts. We provide a framework that unifies transcriptomic and genomic dimensions of metastatic SCLC. The marked differences in transcriptional diversity between patient tumors and model systems are likely to have implications in development of novel therapeutic agents.

Integrative analysis of a large real-world cohort of small cell lung cancer identifies distinct genetic subtypes and insights into histological transformation

“…Furthermore, how specific mutations influence the subtype landscape remains unclear. NE tumors are enriched for alterations in RB1, NOTCH1, MYCL1 , and chromatin modifier genes and these NE tumors may have improved responses to replication stress inhibitors and poorer responses to ICI therapy compared to non-NE tumors (14). However, in this same study, there were no differences in overall survival between patients with NE vs. non-NE tumors, suggesting that the transcriptomic type alone may be insufficient for stratification.…”

“…The largest published study thus far included genome sequencing of 110 SCLC genomes from resected tumors (7). Combining this study and other smaller studies with more limited genomic analyses (e.g., whole-exome sequencing and targeted sequencing such as in (8-14)), it may be possible to get an estimate of genetic alterations in a few hundred patients at best. In addition, the disparate platforms used in these different studies makes it difficult to analyze the data as a group.…”

Subtyping of Small Cell Lung Cancer using plasma cell-free nucleosomes

“…However, transcription factor profiling in clinical tumor samples is challenging, particularly for cancers with limited access to tumor specimens. Recent studies have revealed subtypes of SCLC, the most lethal type of lung cancer, defined by expression of lineage-defining transcription factors and their unique therapeutic vulnerabilities [14][15][16][17][18] . Yet, further testing and broad clinical application of these findings is limited by the availability of tumor tissue, explained by its widely metastatic presentation and aggressive clinical course which precludes surgical resection at diagnosis and tumor biopsies at relapse.…”

“…Recent studies reveal that SCLC tumors are transcriptionally heterogeneous 18,38,39 . We sought to understand whether cfChIP-seq reflects gene expression patterns of SCLC tumors.…”

“…MYC paralogs that drive a broad range of genes related to cell proliferation and growth signaling 12,13 . Importantly, SCLC subtypes driven by distinct transcription factors have unique therapeutic vulnerabilities [14][15][16][17][18] . However, identification of SCLC transcriptomic subtypes and their application in the context of subtype-specific therapies has proven challenging due to limited access to tumor specimens.…”