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R. Ikemori

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    OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA11.06 - Role of Fibroblasts in the Subtype-Specific Therapeutic Effects of Nintedanib in Non-Small Cell Lung Cancer (NSCLC) (ID 5029)

      11:00 - 12:30  |  Author(s): R. Ikemori

      • Abstract
      • Presentation
      • Slides

      There is growing evidence that tumor-associated fibroblasts (TAFs) play a major role in critical steps of tumor progression in solid tumors including NSCLC. However the role of TAFs in regulating the response to targeted therapies is poorly understood. One of such targeted therapies is nintedanib (NTD), a multi-kinase inhibitor of VEGF, FGF and PDGF receptors that has been recently approved to treat advanced lung adenocarcinoma (ADC) patients. Although the therapeutic effects of NTD in lung cancer have been associated with its anti-angiogenic functions, NTD has also been shown to exhibit anti-fibrotic effects in patients with idiopathic pulmonary fibrosis. Since lung fibrosis is largely driven by activated fibroblasts/myofibroblasts, and TAFs are positive for myofibroblasts markers, it is conceivable that NTD anti-tumor effects may be additionally driven through its direct action on lung TAFs. The main goal of this study was to analyze the latter hypothesis.

      Patient derived lung TAFs from ADC and SCC patients as well as paired control fibroblasts from non-malignant pulmonary tissue were exposed to increasing concentrations of NTD and analyzed for growth and activation upon stimulation with growth factors and TGF- β1, respectively. Activation markers included alpha-smooth muscle actin and collagen-I.

      We found that NTD exhibited a dual inhibitory role in TAFs in terms of growth and TGF-β1-induced activation in a subtype-specific fashion. Specifically, NTD-mediated growth inhibition was larger in SCC-TAFs than in ADC-TAFs, which correlated with the larger Erk signaling previously reported by our group in SCC-TAFs in the absence of mitogenic stimuli. Conversely, inhibition by NTD of TGF-β1-mediated activation was larger in ADC-TAFs than SCC-TAFs. Likewise, NTD inhibited the growth and invasive advantages of ADC cancer cells in vitro elicited by the conditioned medium of ADC-TAFs treated with TGF-β1 compared to those advantages elicited in the absence of NTD. These results reveal for the first time that the pro-tumorigenic effects of ADC-TAFs in vitro are markedly reduced in the presence of NTD.

      TAFs in vivo are largely activated and quiescent, and TGF-β1 is a potent fibroblast activator that is frequently upregulated in lung cancer and associated with poor prognosis. Based on these previous observations, we argue that our new findings strongly suggest that the selective therapeutic advantage observed for NTD in ADC patients may be in part related to its selective inhibition of TGF-β1-dependent activation of ADC-TAFs. These findings provide novel mechanistic insights on the subtype-specific therapeutic effects of NTD in NSCLC.

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