Pharmacological inhibition of p38 MAPK reduces tumor growth in patient-derived xenografts from colon tumors.

Jalaj Gupta,Manuel Hidalgo,Angel R Nebreda,Elisabet Llonch,Vassilis G Gorgoulis,Ana Igea,Pedro Pablo Lopez-Casas,Marilena Papaioannou

doi:10.18632/oncotarget.3816

Abstract

Colorectal cancer is a major health problem and the second cause of cancer related death in western countries. Signaling pathways that control tissue homeostasis are often deregulated during tumorigenesis and contribute to tumor development. Studies in mouse models have shown that the p38 MAPK pathway regulates homeostasis in colon epithelial cells but also plays an important role in colon tumor maintenance. In this study, we have investigated the role of p38 MAPK signaling in patient-derived xenografts (PDXs) from three different human colon tumors representing clinical heterogeneity and that recapitulate the human tumor conditions both at histological and molecular levels. We have found that PH797804, a chemical inhibitor of p38 MAPK, reduces tumor growth of the three PDXs, which correlates with impaired colon tumor cell proliferation and survival. The inhibition of p38 MAPK in PDXs results in downregulation of the IL-6/STAT3 signaling pathway, which is a key regulator of colon tumorigenesis. Our results show the importance of p38 MAPK in human colon tumor growth using a preclinical model, and support that inhibition of p38 MAPK signaling may have therapeutic interest for colon cancer treatment.

Highlights

Colorectal cancer (CRC) is the second cause of cancer related mortality in developed countries
We have found that PH797804, a chemical inhibitor of p38 mitogen-activated protein kinase (MAPK), reduces tumor growth of the three patient-derived xenografts (PDXs), which correlates with impaired colon tumor cell proliferation and survival
Taking www.impactjournals.com/oncotarget together, our results indicate that p38 MAPK inhibition does not affect the expression of HER-3 and GABARAP, which are unlikely to contribute to the reduced tumor growth observed in the PDXs from human colon tumors

Summary

INTRODUCTION

Colorectal cancer (CRC) is the second cause of cancer related mortality in developed countries. Tumor induction by AOM can take more than 6 months with tumor multiplicity www.impactjournals.com/oncotarget and penetrance depending on mouse strain and the AOM batch [8] While both APCmin and AOM/DSS models have greatly enhanced our understanding of the basic biology underlying CRC, these models do not allow accurate testing of potential therapies [9]. Unlike many tumor suppressors that are inactivated during the malignant transformation process, inactivating mutations for p38α have not been consistently detected in human solid tumors This probably reflects that tumor cells can benefit from the versatility of this signaling pathway. In line with this idea, p38α signaling has been shown to be important for the survival and proliferation of colon tumor cells in vitro and in mouse models [20, 23,24,25,26] These observations make the p38α pathway a potential therapeutic target. We have used PDXs from three human colorectal tumors with distinct properties and show that inhibition of p38 MAPK signaling reduces colon tumor growth in all cases

RESULTS

DISCUSSION

Statistical methods