Combined Src/EGFR Inhibition Targets STAT3 Signaling and Induces Stromal Remodeling to Improve Survival in Pancreatic Cancer

Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics which hinder the delivery of chemotherapeutic drugs into PDAC tum...

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Vydáno v:	Molecular cancer research Ročník 18; číslo 4; s. 623
Hlavní autoři:	Dosch, Austin R, Dai, Xizi, Reyzer, Michelle L, Mehra, Siddharth, Srinivasan, Supriya, Willobee, Brent A, Kwon, Deukwoo, Kashikar, Nilesh, Caprioli, Richard, Merchant, Nipun B, Nagathihalli, Nagaraj S
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 01.04.2020
Témata:	Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Carcinoma, Pancreatic Ductal - drug therapy Carcinoma, Pancreatic Ductal - metabolism Carcinoma, Pancreatic Ductal - pathology Dasatinib - administration & dosage Dasatinib - pharmacology Deoxycytidine - administration & dosage Deoxycytidine - analogs & derivatives Deoxycytidine - pharmacology Disease Models, Animal ErbB Receptors - antagonists & inhibitors ErbB Receptors - metabolism Erlotinib Hydrochloride - administration & dosage Erlotinib Hydrochloride - pharmacology Female Humans Mice Mice, Nude Pancreatic Neoplasms - drug therapy Pancreatic Neoplasms - metabolism Pancreatic Neoplasms - pathology Protein Kinase Inhibitors - pharmacology Signal Transduction - drug effects src-Family Kinases - antagonists & inhibitors src-Family Kinases - metabolism STAT3 Transcription Factor - antagonists & inhibitors STAT3 Transcription Factor - metabolism Stromal Cells - drug effects Stromal Cells - metabolism Stromal Cells - pathology Survival Analysis Xenograft Model Antitumor Assays
ISSN:	1557-3125, 1557-3125
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Popis
Shrnutí:	Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics which hinder the delivery of chemotherapeutic drugs into PDAC tumors and mediate resistance to therapy. Previously, we have shown that STAT3 is a key biomarker of therapeutic resistance to gemcitabine treatment in PDAC, which can be overcome by combined inhibition of the Src and EGFR pathways. Although it is well-established that concurrent EGFR and Src inhibition exert these antineoplastic properties through direct inhibition of mitogenic pathways in tumor cells, the influence of this combined therapy on stromal constituents in PDAC tumors remains unknown. In this study, we demonstrate in both orthotopic tumor xenograft and (PKT) mouse models that concurrent EGFR and Src inhibition abrogates STAT3 activation, increases microvessel density, and prevents tissue fibrosis . Furthermore, the stromal changes induced by parallel EGFR and Src pathway inhibition resulted in improved overall survival in PKT mice when combined with gemcitabine. As a phase I clinical trial utilizing concurrent EGFR and Src inhibition with gemcitabine has recently concluded, these data provide timely translational insight into the novel mechanism of action of this regimen and expand our understanding into the phenomenon of stromal-mediated therapeutic resistance. IMPLICATIONS: These findings demonstrate that Src/EGFR inhibition targets STAT3, remodels the tumor stroma, and results in enhanced delivery of gemcitabine to improve overall survival in a mouse model of PDAC.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1557-3125 1557-3125
DOI:	10.1158/1541-7786.MCR-19-0741