1810P - MYC expression defines distinct transcriptomic landscape and affects response to DNA-damaging therapies in SCLC

Background

Small cell lung cancer (SCLC) is characterized by TP53/RB1 loss and amplification of MYC in approximately 30% of patients. DNA damaging therapies synergize with immunotherapy in SCLC in in vivo models by activating a Stimulator of Interferon Genes (STING)-mediated immune response. In addition, MYC is known to be positively correlated with STING pathway downstream chemokines (CXCL10 and CCL5) in SCLC clinical datasets. Here we aimed to define the transcriptional profile of SCLC cell lines in relation to MYC expression levels.

Methods

We performed GSEA on RNAseq data obtained from n=6 SCLC cell lines classified as MYClow or MYChigh before and after treatment with cisplatin. We validated transcriptomic data by immunofluorescence, flow cytometry and western blot.

Results

GSEA revealed enrichment of immune-related pathways, including type I interferon response, interleukins and chemokines response gene sets in MYChigh cells. Epithelial markers, cell adhesion molecules and stemness downregulation datasets were also enriched in MYChigh subset. In constrast, MYClow SCLC cell lines were particularly enriched for glycolysis and mesenchymal gene sets. In addition, STING and PD-L1 protein expression was higher in MYChigh compared to MYClow SCLC cells. Cisplatin treatment affected transcriptomic profile of MYChigh subset by increasing DNA repair, aerobic respiration and innate immune pathways related to viral infections. Interestingly, GSEA of cisplatin-treated MYClow showed enrichment in chemotherapy-resistance genes along with increase of proliferation and lung cancer poor survival. In addition, cisplatin-treated MYClow showed an increase in AURKA and ATR genesets. In parallel, in vitro treatment with cisplatin increased STING expression in MYChigh cells, while it decreased or had no effect on STING in MYClow cells.

Conclusions

SCLC cells with different MYC levels display distinct transcriptomic landscapes. Overall, MYChigh cells are more responsive to innate immune cell activation. In contrast, MYClow cells exhibit more mesenchymal and chemotherapy-resistant features. Finally, the AURKA/ATR pathway in the MYClow subset may be potential candidates for combination therapies in cisplatin-resistant SCLC models.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

AIRC.

Disclosure

All authors have declared no conflicts of interest.