A tumour-promoting senescent secretome triggered by 1 platinum chemotherapy 2 exploits a targetable TGFbR1/Akt-mTOR axis in lung cancer

Platinum-based chemotherapeutic regimens are standard treatments for non-small cell lung cancer 45 (NSCLC) patients, but long-term clinical outcomes remain poor. Cellular senescence and its associated 46 secretory phenotype (SASP) can have multiple tumour-promoting activities, although these are largely 47 unexplored in lung cancer. Here we show that cisplatin-derived SASP leads to an enhanced malignant 48 phenotype in lung cancer cells. In vivo functional analyses in xenograft, orthotopic and KRAS-driven 49 murine lung cancer models demonstrate that cisplatin-induced senescent cells strongly promote tumour 50 progression. Mechanistically, we find that a SASP enriched in TGF-ß ligands drives pro-proliferative 51 effects through TGFßR1 and Akt/mTOR pathway activation. We validate the translational relevance 52 of chemotherapy-induced SASP by analysing clinical NSCLC samples from patients who received 53 neoadjuvant platinum-based chemotherapy. We show that pharmacologic inhibition of TGFßR1 with 54 galunisertib, as well as senolytic treatment, significantly reduces tumour-promoting effects driven by 55 cisplatin-induced senescence. Finally, we demonstrate, using distinct murine lung cancer models, that 56 addition of TGFßR1 inhibitors to platinum-based chemotherapy reduces tumour burden and improves 57 survival, providing proof-of-concept for this therapeutic approach for future clinical trial design.