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EMBO Mol Med. 2015 Jun;7(6):735-53. doi: 10.15252/emmm.201404346.

Pharmacological targeting of the protein synthesis mTOR/4E-BP1 pathway in cancer-associated fibroblasts abrogates pancreatic tumour chemoresistance.

Author information

1
INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France.
2
INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France Biochemistry-Immunology Laboratory, Faculty of Sciences Rabat, University Mohammed V - Agdal, Agdal, Morocco.
3
EA 3842 Laboratory, Medicine and Pharmacy Faculties, Limoges University, Limoges, France.
4
Pathology Department, Hôpitaux de Toulouse, Toulouse, France.
5
CNRS UMR-5089, Institut de Pharmacologie et de Biologie structurale (IPBS), Université de Toulouse, Toulouse, France.
6
CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM105; CNRS, UMR7258, Marseille, France.
7
Novartis Pharmaceuticals, Bales, Switzerland.
8
INSERM UMR-1037, Cancer Research Center of Toulouse (CRCT), Equipe labellisée Ligue Contre le Cancer and Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Université de Toulouse, Toulouse, France corinne.bousquet@inserm.fr.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is extremely stroma-rich. Cancer-associated fibroblasts (CAFs) secrete proteins that activate survival and promote chemoresistance of cancer cells. Our results demonstrate that CAF secretome-triggered chemoresistance is abolished upon inhibition of the protein synthesis mTOR/4E-BP1 regulatory pathway which we found highly activated in primary cultures of α-SMA-positive CAFs, isolated from human PDAC resections. CAFs selectively express the sst1 somatostatin receptor. The SOM230 analogue (Pasireotide) activates the sst1 receptor and inhibits the mTOR/4E-BP1 pathway and the resultant synthesis of secreted proteins including IL-6. Consequently, tumour growth and chemoresistance in nude mice xenografted with pancreatic cancer cells and CAFs, or with pieces of resected human PDACs, are reduced when chemotherapy (gemcitabine) is combined with SOM230 treatment. While gemcitabine alone has marginal effects, SOM230 is permissive to gemcitabine-induced cancer cell apoptosis and acts as an antifibrotic agent. We propose that selective inhibition of CAF protein synthesis with sst1-directed pharmacological compounds represents an anti-stromal-targeted therapy with promising chemosensitization potential.

KEYWORDS:

cancer‐associated fibroblasts; chemoresistance; pancreatic cancer; pharmacotherapy; protein synthesis and secretion

PMID:
25834145
PMCID:
PMC4459815
DOI:
10.15252/emmm.201404346
[Indexed for MEDLINE]
Free PMC Article

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