Open AccessTargeting the LOX / hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy
Author(s) -
Miller Bryan W,
Morton Jennifer P,
Pinese Mark,
Saturno Grazia,
Jamieson Nigel B,
McGhee Ewan,
Timpson Paul,
Leach Joshua,
McGarry Lynn,
Shanks Emma,
Bailey Peter,
Chang David,
Oien Karin,
Karim Saadia,
Au Amy,
Steele Colin,
Carter Christopher Ross,
McKay Colin,
Anderson Kurt,
Evans Thomas R Jeffry,
Marais Richard,
Springer Caroline,
Biankin Andrew,
Erler Janine T,
Sansom Owen J
Publication year - 2015
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201404827
Subject(s) - estate , cancer drugs , library science , pancreatic cancer , cancer , medicine , political science , law , computer science
Pancreatic ductal adenocarcinoma ( PDAC ) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis ( PCA ), we identified a LOX /hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre Kras G12D/+ Trp53 R172H/+ ( KPC ) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease.