PO-001 Therapeutic inhibition of trefoil factor 3(TFF3) decrease oncogenic behaviour in non-small cell lung cancer (NSCLC)

• Published in: ESMO open Vol. 3; no. Suppl 2; p. A228
• Main Authors: Zhang, M, Chong, QY, Pandey, V, Chen, RM, Basappa, S, Goh, BC, Lobie, PE
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01-07-2018
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1136/esmoopen-2018-EACR25.539

IntroductionIncreasing evidence has shown that trefoil factor 3 (TFF3) is increased in expression in various cancers and promotes cancer progression. Elevated TFF3 levels have been reported in lung cancer patients. TFF3, which is expressed in the vast majority of lung adenocarcinomas (ADC), has also been proposed as a novel biomarker to distinguish between lung ADC and squamous-cell carcinoma (SCC). Herein, we investigated the oncogenic functions of TFF3 and explored the potential of therapeutic TFF3 inhibition in NSCLC.Material and methodsThe function of TFF3 in lung ADC was investigated by either forced or depleted expression of TFF3 in H1299 and H1975 cell lines. Cell functional assays performed include total cell count, PI-Annexin V apoptosis assay, cell cycle analysis, soft agar colony formation, 3Dgrowth in Matrigel, wound healing and transwell migration and invasion assays. A novel small molecule TFF3 inhibitor, AMPC, has been developed in and was used to examine the functional effects of TFF3 inhibition in the lung ADC cells, both as a single agent and in combination with MEK1/2 inhibitors. The paracrine effect of local TFF3 production by lung ADC cells on non-TFF3 expressing lung SCC cells was examined using co-culture assays.Results and discussionsThe forced expression of TFF3 enhanced cell proliferation and survival, increased anchorage-independent growth, and promoted cell migration and invasion in lung ADC cells. In contrast, the siRNA-mediated depletion of TFF3 expression decreased the oncogenicity of these cells. Consistently, the inhibition of TFF3 by AMPC resulted in markedly decreased cell survival, proliferation, 3D growth and foci formation of lung ADC cells. Expression of the proto-oncogene ARAF was increased by forced expression of TFF3 in lung ADC cells, with consequent increased activation of downstream MEK1/2 and ERK1/2. This TFF3-mediated activation of the MAPK/ERK pathway was required for TFF3-stimulated 3D-growth of lung ADC cells. Moreover, the combination of MEK1/2 inhibitors with AMPC exhibited synergistic inhibitory effects in lung ADC cells. In addition, we demonstrated that the local secretion of TFF3 from lung ADC cells exerts paracrine effects on lung SCC cells, which is relevant in the adenosquamous carcinoma (ASC) subtype of NSCLC.ConclusionTFF3 is a crucial oncogene in NSCLC progression.The therapeutic inhibition of TFF3 alone or in combination with conventional MEK1/2 inhibitors are potential strategies in the treatment of NSCLC.