140P - MYC subgroups delineate specific transcriptomic landscape and shape response to radiotherapy in SCLC

Background

Thoracic radiotherapy (TRT) has been widely used in the treatment of extensive-stage small cell lung cancer (ES-SCLC). However, this approach to treatment has been excluded from the phase III trials that investigated chemotherapy (CT) + anti-PD-L1 in the first-line setting. Recently, the use of TRT as a boost to the antitumor immune response through stimulator of interferon genes (STING) activation has been reported. However, the role of TRT in combination with CT in mediating the switch of SCLC towards the immune-responsive SCLC is still unclear. Here, we characterised the transcriptional profile following treatment with RT alone or in combination with CT in MYChigh versus MYClow SCLC cell lines.

Methods

We performed GSEA on RNAseq data obtained from n=6 SCLC cell lines classified as MYClow or MYChigh before and after treatment with CT (cisplatin 0.5 uM) and/or RT (4 Gy) for 72h. STING activation in SCLC cells was explored by immunofluorescence, flow cytometry and western blot to validate transcriptomic data.

Results

GSEA revealed that RT-treated MYChigh cells were enriched for STING-related pathways, including IRF3/IRF7/TBK1 gene sets compared to CT. E-cadherin targets and metastasis data sets were downregulated in the RT-treated MYChigh compared to CT. The combination of RT+CT resulted in enrichment of IFN-related pathways and upregulation of YAP1 gene sets compared to CT alone in MYChigh cells, suggesting a switch towards an immune-responsive phenotype. RT-treated MYClow SCLC cell lines were particularly enriched for E2F targets and lung cancer poor survival gene sets in comparison to CT treatment. Furthermore, CT+RT combination treatment affected MYClow transcriptomic profile by increasing EMT markers, MYC oncogenic signature and decreasing YAP1 and IFN-related pathways compared to CT. The NE marker NEUROD1 was also significantly upregulated in MYClow cells after RT+CT treatment. In parallel, in vitro cisplatin-treatment increased STING expression preferentially in MYChigh cells.

Conclusions

MYClow cells exhibit mesenchymal and resistant features. MYChigh cells are more responsive to the activation of innate immune cells and are more likely to benefit from the addition of RT to CT by switching to the inflamed SCLC YAP1 subtype.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

AIRC, Fondazione Italiana per la Ricerca sul Cancro.

Disclosure

All authors have declared no conflicts of interest.