Abstract
Simple SummaryThere is currently no effective treatment for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Transforming Growth Factor β (TGFβ) signaling has been implicated in several hallmark features of PDAC pathobiology, and TGFβ inhibitors are beginning to show promise in the treatment of PDAC. Here, we discuss the known roles of TGFβ signaling in the pancreatic tumor microenvironment, as well as clinical trials evaluating TGFβ pathway inhibitors in PDAC patients.Pancreatic ductal adenocarcinoma (PDAC) is associated with poor clinical outcomes, largely attributed to incomplete responses to standard therapeutic approaches. Recently, selective inhibitors of the Transforming Growth Factor β (TGFβ) signaling pathway have shown early promise in the treatment of PDAC, particularly as a means of augmenting responses to chemo- and immunotherapies. However, TGFβ is a potent and pleiotropic cytokine with several seemingly paradoxical roles within the pancreatic tumor microenvironment (TME). Although TGFβ signaling can have potent tumor-suppressive effects in epithelial cells, TGFβ signaling also accelerates pancreatic tumorigenesis by enhancing epithelial-to-mesenchymal transition (EMT), fibrosis, and the evasion of the cytotoxic immune surveillance program. Here, we discuss the known roles of TGFβ signaling in pancreatic carcinogenesis, the biologic consequences of the genetic inactivation of select components of the TGFβ pathway, as well as past and present attempts to advance TGFβ inhibitors in the treatment of PDAC patients.
Highlights
Published: 11 October 2021Despite significant progress for several difficult-to-treat malignancies in recent years, there is currently no effective treatment for pancreatic ductal adenocarcinoma (PDAC).While broad-spectrum chemotherapy can modestly extend survival for most patients, most will eventually progress during treatment [1], and overall five-year survival remains at a dismal 10% [2]
This is consistent with clinical observations that p21 positively associates with both SMAD4 and TGFβ1 [25], and that PDAC patients with robust p21 expression have improved prognosis [25]
Leucine-Rich Repeat Containing 15 (LRRC15). These LRRC15-expressing myofibroblastic CAFs (myCAFs)-like cells contribute to the failure of immune checkpoint inhibition in PDAC, which is consistent with previous observations suggesting that transforming growth factor β (TGFβ)-induced extracellular matrix (ECM) genes link CAFs to immune evasion and the failure of cancer immunotherapy [136,137]
Summary
Despite significant progress for several difficult-to-treat malignancies in recent years, there is currently no effective treatment for pancreatic ductal adenocarcinoma (PDAC). The poor clinical outcomes associated with PDAC largely stem from a late stage of diagnosis, the lack of an effective screening modality, and widespread drug resistance [1,3,4]. This highlights an urgent need for new therapeutic approaches in order to improve outcomes for what is largely considered an incurable disease. To this end, transforming growth factor β (TGFβ) is emerging as a key mediator of the PDAC tumor microenvironment (TME). We discuss the known elements of TGFβ signaling in PDAC, as well as past and present attempts to advance therapies targeting the TGFβ pathway in clinical trial
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