1800P - Breaking chemo-immunotherapy resistance in SCLC-patient derived tumor with novel DDRi combinations

Background

Chemoimmunotherapy (CIT) is the standard first-line therapy for patients with extensive-stage small cell lung cancer (SCLC). Recent evidence defined a subtype of SCLC patients who respond to CIT classified as "inflamed” expressing high levels of innate immune genes such as the STimulator of INterferon pathway (STING). Further preclinical data support DNA damage response (DDR) inhibition, in particular DNA-PKi, in promoting STING-mediated anti-tumour immunity in SCLC. Here we aimed to investigate novel combinations of DDRi as treatment options for CIT-resistant SCLC patients.

Methods

Considering the low availability of tissue material from SCLC patients, we established cancer cell cultures derived from the pleural effusion of a CIT-resistant SCLC patient. Culture populations contained both floating and adherent cells, floating cells were collected by centrifugation of the medium and redispersed. Primary cell lines were treated with cisplatin + atezolizumab for 24h, followed by DDRi treatment for a further 72h. Cell viability was evaluated by MTS assay. DDR and STING mRNA and protein expression was assessed by RT-PCR and Western blot.

Results

We confirmed CIT resistance of SCLC patient-derived cell lines by cell viability assay (75% cell viability). High expression of DDR proteins (DNA-PK, ATR, XRCC5 and XRCC6) were detected in SCLC pleural effusion-derived cell lines. Interestingly, STING-related immune pathways and PD-L1/PD-1 expression were reduced after treatment with CIT in SCLC pleural effusion-derived cell lines. The sequential treatment with CIT followed by DNA-PKi alone did not affect cell viability. We then screened sequential treatment with CIT followed by two combined DDRis. In particular, among the combinations tested, we found that CIT followed by DNA-PKi plus ATRi was most effective in activating the STING-related immune pathway and inducing a significant reduction in % cell viability (P<0.001).

Conclusions

We demonstrated in pleural effusion-derived cell lines of CIT-resistant SCLC a significant positive modulation of STING-mediated immune pathways with both CIT followed by DNA-PKi plus ATRi, providing evidence of a possible positive role of DDRi combinations in SCLC patients resistant to CIT.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

AIRC.

Disclosure

All authors have declared no conflicts of interest.