Abstract 5504: A tumor-promoting senescent secretome triggered by platinum chemotherapy exploits a targetable TGFβR1/Akt-mTOR axis in lung cancer
Authors: González-Gualda Estela , Macias David , Morsli Samir , Martín José Ezequiel , Ou Hui-Ling , Denholm Mary , Olan Ioana , Hoffmann Reuben , Dane Mark , Veroutis Dimitris , Medrano Guillermo , Mulero Francisca , Martins Carla P. , Barbacid Mariano , Gorgoulis Vassilis , Korkola James E. , Rassl Doris M. , Doherty Gary J. , Rintoul Robert C. , Narita Masashi , Muñoz-Espín Daniel 
Published: June 2023

Background Platinum-based chemotherapy is commonly used for the treatment of non-small cell lung cancer (NSCLC), yet clinical outcomes and survival rates remain very poor and continues to be a cancer of unmet need. Recent evidence points to cellular senescence, a response to oncogenic- and therapy-induced genotoxic stress, and its associated proinflammatroy secretory phenotype (SASP) as an emerging hallmark of cancer. Hence, targeting senescence and its associated tumor-promoting activities is emerging as a novel and promising therapeutic strategy but largely unexplored in lung cancer.

Experimental Procedures Our study includes a variety of methodologies, including: - Functional in vitro analyses: proliferation, colony formation, tumor spheres, migration assays. High throughput unbiased analyses: RNAseq, proteomics and microenvironment microarrays (MEMA). - In vivo models of lung cancer: xenografts, orthotopic and genetically engineered mouse models. Longitudinal tumor burden by IVIS and microCT and mouse survival. - Clinical samples: Histological and in silico analyses.

Results Here we show that cisplatin-derived SASP enhances the malignant phenotype of lung cancer cells. Using xenograft, orthotopic and KrasG12V-driven murine NSCLC models, we demonstrate that cisplatin-induced senescent cells strongly promote tumor progression. Mechanistically, we find that a TGF-β-enriched SASP drives pro-proliferative effects through TGFβR1 and Akt/mTOR pathway activation. We validate the translational relevance of chemotherapy-induced SASP using clinical NSCLC samples from a trial with patients who received neoadjuvant platinum-based chemotherapy. Importantly, TGFβR1 inhibition with galunisertib or senolytic treatment significantly reduces tumor promotion driven by cisplatin-induced senescence. Finally, we demonstrate, using distinct murine NSCLC models, that addition of TGFBR1 inhibitors to platinum-based chemotherapy reduces tumor burden and improves survival, providing pre-clinical proof-of-concept for future trial designs on combination therapies.

Conclusions and Impact We regard this work as a major conceptual dissection of tumor-promoting activities of therapy-induced senescence, and a preclinical advance in the management of lung cancer with potential wide therapeutic applications in precision medicine. Of note, we expect our findings to have implications for multiple cancer types, including ovarian, breast, mesothelioma, oesophageal, head and neck, bladder and brain cancers, where platinum-based therapies remain important standard-of-care treatments.

Citation Format: Estela González-Gualda, David Macias, Samir Morsli, José Ezequiel Martín, Hui-Ling Ou, Mary Denholm, Ioana Olan, Reuben Hoffmann, Mark Dane, Dimitris Veroutis, Guillermo Medrano, Francisca Mulero, Carla P. Martins, Mariano Barbacid, Vassilis Gorgoulis, James E. Korkola, Doris M. Rassl, Gary J. Doherty, Robert C. Rintoul, Masashi Narita, Daniel Muñoz-Espín. A tumor-promoting senescent secretome triggered by platinum chemotherapy exploits a targetable TGFβR1/Akt-mTOR axis in lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5504.