Dataset Information

Targeting TGF?R2-mutant tumors exposes vulnerabilities to stromal TGF? blockade in pancreatic cancer.

ABSTRACT: TGF? is important during pancreatic ductal adenocarcinoma (PDA) progression. Canonical TGF? signaling suppresses epithelial pancreatic cancer cell proliferation; as a result, inhibiting TGF? has not been successful in PDA. In contrast, we demonstrate that inhibition of stromal TGF?R2 reduces IL-6 production from cancer-associated fibroblasts, resulting in a reduction of STAT3 activation in tumor cells and reversion of the immunosuppressive landscape. Up to 7% of human PDA have tumor cell-specific deficiency in canonical TGF? signaling via loss of TGF?R2. We demonstrate that in PDA that harbors epithelial loss of TGF?R2, inhibition of TGF? signaling is selective for stromal cells and results in a therapeutic benefit. Our study highlights the potential benefit of TGF? blockade in PDA and the importance of stratifying PDA patients who might benefit from such therapy.

SUBMITTER: Huang H

PROVIDER: S-EPMC6835203 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer.

Huang Huocong H Zhang Yuqing Y Gallegos Valerie V Sorrelle Noah N Zaid Mohamed Medhat MM Toombs Jason J Du Wenting W Wright Steven S Hagopian Moriah M Wang Zhaoning Z Hosein Abdel Nasser AN Sathe Adwait Amod AA Xing Chao C Koay Eugene J EJ Driscoll Kyla E KE Brekken Rolf A RA

EMBO molecular medicine 20191014 11

TGFβ is important during pancreatic ductal adenocarcinoma (PDA) progression. Canonical TGFβ signaling suppresses epithelial pancreatic cancer cell proliferation; as a result, inhibiting TGFβ has not been successful in PDA. In contrast, we demonstrate that inhibition of stromal TGFβR2 reduces IL-6 production from cancer-associated fibroblasts, resulting in a reduction of STAT3 activation in tumor cells and reversion of the immunosuppressive landscape. Up to 7% of human PDA have tumor cell-specifi ...[more]

PMID: 31609088

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Project description:UnlabelledSummaryGastrointestinal stromal tumors (GISTs) represent 20%-40% of human sarcomas. Although approximately half of GISTs are cured by surgery, prognosis of advanced disease used to be poor due to the high resistance of these tumors to conventional chemo- and radiotherapy. The introduction of molecularly targeted therapy (e.g., with imatinib mesylate) following the discovery of the role of oncogenic mutations in the receptor tyrosine kinases KIT and platelet-derived growth factor α (PDGFRA) significantly increased patient survival. However, GIST cells persist in 95%-97% of imatinib-treated patients who eventually progress and die of the disease because of the emergence of clones with drug-resistant mutations. Because these secondary mutations are highly heterogeneous, even second- and third-line drugs that are effective against certain genotypes have only moderately increased progression-free survival. Consequently, alternative strategies such as targeting molecular mechanisms underlying disease persistence should be considered. We reviewed recently discovered cell-autonomous and microenvironmental mechanisms that could promote the survival of GIST cells in the presence of tyrosine kinase inhibitor therapy. We particularly focused on the potential role of adult precursors for interstitial cells of Cajal (ICCs), the normal counterpart of GISTs. ICC precursors share phenotypic characteristics with cells that emerge in a subset of patients treated with imatinib and in young patients with GIST characterized by loss of succinate dehydrogenase complex proteins and lack of KIT or PDGFRA mutations. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to tumor genotype and phenotype.SignificanceGastrointestinal stromal tumors (GISTs) are one of the most common connective tissue cancers. Most GISTs that cannot be cured by surgery respond to molecularly targeted therapy (e.g., with imatinib); however, tumor cells persist in almost all patients and eventually acquire drug-resistant mutations. Several mechanisms contribute to the survival of GIST cells in the presence of imatinib, including the activation of "escape" mechanisms and the selection of stem-like cells that are not dependent on the expression of the drug targets for survival. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to the genetic makeup and other characteristics of the tumors.

Dataset Information

Targeting TGF?R2-mutant tumors exposes vulnerabilities to stromal TGF? blockade in pancreatic cancer.

Publications

Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer.

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