Dual inhibition of TGF[beta] and AXL as a novel therapy for human colorectal adenocarcinoma with mesenchymal phenotype.

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From: Medical Oncology(Vol. 38, Issue 3)
Publisher: Springer
Document Type: Report; Brief article
Length: 360 words

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Keywords: AXL; TGF[beta]; Colorectal cancer; EMT Abstract A subset of colorectal cancer (CRC) with a mesenchymal phenotype (CMS4) displays an aggressive disease, with an increased risk of recurrence after surgery, reduced survival, and resistance to standard treatments. It has been shown that the AXL and TGF[beta] signaling pathways are involved in epithelial-to-mesenchymal transition, migration, metastatic spread, and unresponsiveness to targeted therapies. However, the prognostic role of the combination of these biomarkers and the anti-tumor effect of AXL and TGF[beta] inhibition in CRC still has to be assessed. To evaluate the role of AXL and TGF[beta] as negative biomarker in CRC, we conducted an in-depth in silico analysis of CRC samples derived from the Gene Expression Omnibus. We found that AXL and TGF[beta] receptors are upregulated in CMS4 tumors and are correlated with an increased risk of recurrence after surgery in stage II/III CRC and a reduced overall survival. Moreover, we showed that AXL receptor is differently expressed in human CRC cell lines. Dual treatment with the TGF[beta] galunisertib and the AXL inhibitor, bemcentinib, significantly reduced colony formation and migration capabilities of tumor cells and displayed a strong anti-tumor activity in 3D spheroid cultures derived from patients with advanced CRC. Our work shows that AXL and TGF[beta] receptors identify a subgroup of CRC with a mesenchymal phenotype and correlate with poor prognosis. Dual inhibition of AXL and TGF[beta] could represent a novel therapeutic strategy for patients with this aggressive disease. Author Affiliation: (1) Medical Oncology, Department of Precision Medicine, Università Degli Studi Della Campania Luigi Vanvitelli, Napoli, Campania, Italy (2) Department of Medicine I, Comprehensive Cancer Center, Research, Medical University of Vienna, Vienna, Austria (3) Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria (4) General and Oncologic Surgery, Department of Medical, Surgical, Neurologic, Metabolic and Ageing Sciences, Università Degli Studi Della Campania Luigi Vanvitelli, Napoli, Campania, Italy (5) Pathology Unit, Department of Mental and Physical Health and Preventive Medicine, Università Degli Studi Della Campania Luigi Vanvitelli, Napoli, Campania, Italy (6) Gastroenterology Unit, Ospedale Umberto I, Nocera Inferiore, Italy (aa) erikamartinelli@yahoo.it Article History: Registration Date: 01/13/2021 Received Date: 08/28/2020 Accepted Date: 01/12/2021 Online Date: 02/11/2021 Byline:

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Gale Document Number: GALE|A651561668