Abstract 3085
Background
AXL and transforming growth factor β (TGF-β) signalling pathways play a key role in modulating tumour microenvironment by promoting epithelial to mesenchymal transition (EMT), stromal activation and regulating immune response in colorectal cancer (CRC). Here we have evaluated the effect of double blockade of TGF-β and AXL receptors, as an innovative therapeutic strategy for CRC.
Methods
We assessed the correlation of TGF-β and AXL by an in silico analysis of a human CRC gene expression profile database. Afterwards, an evaluation of AXL expression of in a panel of human CRC cell lines by Western Blot (WB) and Real time PCR was performed. The sensitivity of HCT116 and LOVO cells to treatment with galunisertib (LY21209761), a TGF-β R1 inhibitor, and R428, an AXL inhibitor, was assessed by MTT, cell migration, and colony forming assays. Furthermore we generated patient derived 3D spheroid cultures from primary CRC, and tested their susceptibility to galunisertib and R428 by MTT assay. Finally, in vivo experiments were done with HCT116 and LOVO tumour xenografts in immunodeficient mice.
Results
In silico analysis showed an association between high expression levels of AXL and TGF-β R1 in CMS4 CRC. AXL was differently expressed on cell lines, and interestingly it resulted increased in HCT116 and LOVO after TGF-β inhibition, probably representing a mechanism of cancer cell escape. Dual blockade with galunisertib and R428 determined a reduction in cell migration of 50% in HCT116 and 37% in LOVO cells, respectively, and colony formation of approximately 90 % in both cell lines. Moreover, combined treatment displayed a strong synergistic activity in 3D cultures derived from five human CRC samples, resulting in the inhibition of proliferation ranging from 80 to 90%. The in vivo experiments of HCT116 and LOVO subcutaneous xenograft models are currently on going and results will be presented.
Conclusions
Combined TGF-β and AXL inhibition showed a promising activity in preclinical models of CRC and could represent a novel potential therapeutic strategy for patients with CRC.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Università degli studi della Campania "Luigi Vanvitelli".
Funding
ICURE project, Università degli studi della Campania "Luigi Vanvitelli".
Disclosure
D. Melisi: Research grant/Funding (self): Lilly.
Resources from the same session
5052 - Identification of first-in-class, naturally occurring LAG3 checkpoint inhibitor
Presenter: Gennady Bratslavsky
Session: Poster Display session 1
Resources:
Abstract
5336 - Are Epigenetic therapies modifying sensitivity to conventional chemotherapy?
Presenter: Alexandra Bizot
Session: Poster Display session 1
Resources:
Abstract
5739 - Oncogenic mutations at the dimer interface of EGFR lead to formation of covalent homo-dimers and allosteric activation of the kinase domain: A mechanism which alters the selectivity profile of oncogenic EGFR.
Presenter: Elizabeth Buck
Session: Poster Display session 1
Resources:
Abstract
5492 - Basic selective estrogen receptor degraders (B-SERDs) in combination with novel BET inhibitors in ER+ breast cancer
Presenter: Rui Xiong
Session: Poster Display session 1
Resources:
Abstract
5965 - EPI-7386 is a novel N-terminal domain androgen receptor inhibitor for the treatment of prostate cancer
Presenter: Ronan Le Moigne
Session: Poster Display session 1
Resources:
Abstract
3582 - AVID200 neutralizes TGF-beta1 and -beta3, the principal immunosuppressive TGF-beta isoforms overexpressed by tumors, and sensitizes tumors to immune checkpoint inhibitors.
Presenter: Tina Gruosso
Session: Poster Display session 1
Resources:
Abstract
1996 - High NAMPT expression and anti-tumor activity of NAMPT inhibitor in adult T-cell leukemia/lymphoma
Presenter: Tomohiro Kozako
Session: Poster Display session 1
Resources:
Abstract
4307 - TPX-0046 is a novel and potent RET/SRC inhibitor for RET-driven cancers
Presenter: Alexander Drilon
Session: Poster Display session 1
Resources:
Abstract
4869 - In Vivo Evaluation of Cisplatin-loaded PEG-PCL Block Copolymeric Nanoparticles for Anticancer Drug Delivery
Presenter: Yingtzu Yen
Session: Poster Display session 1
Resources:
Abstract
5054 - Inhibition of Rspo-Wnt pathway Facilitates Checkpoint Blockade Therapy by anti-RSPO3 antibody (DBPR117)
Presenter: John Hsu
Session: Poster Display session 1
Resources:
Abstract