FAT1: a potential target for monoclonal antibody therapy in colon cancer.
Colorectal cancer (CRC) is one of the major causes of cancer-associated mortality worldwide. The currently approved therapeutic agents have limited efficacy.



The atypical cadherin FAT1 was discovered as a novel CRC-associated protein by using a monoclonal antibody (mAb198.3). FAT1 expression was assessed in CRC cells by immunohistochemistry (IHC), immunoblots, flow cytometry and confocal microscopy. In addition, in vitro and in vivo tumour models were done to assess FAT1 potential value for therapeutic applications.



The study shows that FAT1 is broadly expressed in primary and metastatic CRC stages and detected by mAb198.3, regardless of KRAS and BRAF mutations. FAT1 mainly accumulates at the plasma membrane of cancer cells, whereas it is only marginally detected in normal human samples. Moreover, the study shows that FAT1 has an important role in cell invasiveness while it does not significantly influence apoptosis. mAb198.3 specifically recognises FAT1 on the surface of colon cancer cells and is efficiently internalised. Furthermore, it reduces cancer growth in a colon cancer xenograft model.



This study provides evidence that FAT1 and mAb198.3 may offer new therapeutic opportunities for CRC including the tumours resistant to current EGFR-targeted therapies.
Externautics SpA, Siena, Italy.
Piero
P
Pileri
Externautics SpA, Siena, Italy.
Susanna
S
Campagnoli
Externautics SpA, Siena, Italy.
Alberto
A
Grandi
Externautics SpA, Siena, Italy.
Matteo
M
Parri
European Institute of Oncology, Milan, Italy.
Elisa
E
De Camilli
The Fourth Military Medical University, Xi'an, China.
Chaojun
C
Song
Externautics SpA, Siena, Italy.
Luisa
L
Ganfini
Medical Center, Basel University, Basel, Switzerland.
Aurelien
A
Lacombe
IFC-CNR, Siena, Italy.
Ilaria
I
Naldi
Externautics SpA, Siena, Italy.
Paolo
P
Sarmientos
IFC-CNR, Siena, Italy.
Caterina
C
Cinti
The Fourth Military Medical University, Xi'an, China.
Boquan
B
Jin
Externautics SpA, Siena, Italy.|University of Trento, Trento, Italy.
Guido
G
Grandi
European Institute of Oncology, Milan, Italy.|University of Milan, Milan, Italy.
Giuseppe
G
Viale
Medical Center, Basel University, Basel, Switzerland.
Luigi
L
Terracciano
Externautics SpA, Siena, Italy.
Renata
R
Grifantini
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D009154:Mutation / Q000187:drug effects; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015820:Cadherins; C502403:FAT1 protein, human; D066246:ErbB Receptors; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins