Nintedanib is a clinically-approved multikinase receptor inhibitor that, in combination with docetaxel, provides clinical benefits to advanced lung adenocarcinoma (ADC) patients but not to lung squamous cell carcinoma (SCC) patients. However, the mechanisms underlying the selective therapeutic effects of Nintedanib in ADC remain poorly understood. Of note, Nintedanib is also approved to treat patients with idiopathic pulmonary fibrosis (IPF), a rare disease characterised by an abundant desmoplastic stroma rich in pathologically activated fibroblasts. Since the tumor stroma in lung cancer is also desmoplastic, and we recently showed that tumor-associated fibroblasts (TAFs) derived from ADC and SCC patients exhibit different phenotypes in vitro, we hypothesized that TAFs may underlie the selective effects of Nintedanib in ADC. To test this hypothesis we activated TAFs in culture with the pro-fibrotic cytokine TGF-β1 in the presence of increasing concentrations of Nintedanib, and collected the corresponding conditioned medium. Remarkably SCC-TAFs showed very modest inhibition of a panel of fibrotic markers including α-SMA, P4HA2 and fibrillar collagens (COL1A1, COL3A) in response to Nintedanib, in striking contrast to ADC-TAFs and paired lung parenchyma fibroblasts, which were markedly affected. This was matched by a significant reduction in the abilities of the conditioned medium of ADC-TAFs but not SCC-TAFs to promote cancer cell growth and invasion in a panel of lung cancer cell lines after Nintedanib treatment. These results reveal that Nintedanib is an effective inhibitor of stromal fibrosis and its associated tumor-promoting effects in ADC, and that the poor antifibrotic response of SCC-TAFs to Nintedanib may contribute to the differential clinical benefit observed in both subtypes. Our findings also support that TGF-β signalling and aberrant TAF-carcinoma cross-talk are regulated by different mechanisms in ADC and SCC. In addition they support that preclinical models based on carcinoma-TAF interactions may help defining the mechanisms of the poor antifibrotic response of SCC-TAFs to Nintedanib and testing new combined therapies to further expand the therapeutic effects of this drug in solid tumors.

Citation Format: Jordi Alcaraz, Marta Gabasa, Rafael Ikemori, Frank Hilberg, Noemí Reguart. Nintedanib abrogates the activation and tumor-promoting effects of fibroblasts from lung adenocarcinoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2869.