Abstract
Simple SummaryOncogenic KRAS signaling drives several effector cascades that contribute not only to the malignant behavior of pancreatic cancer cells but also formation of the fibro-inflammatory microenvironment. The non-neoplastic cells in the tumor microenvironment interact with tumor cells, creating a complex onco-inflammatory signaling network that enhances the resilience of cancer cells and potentially explaining why targeting KRAS effectors is clinically ineffective. We provide a focused review of this onco-inflammatory network and discuss novel therapeutic opportunities that can be developed.Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the KRAS oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network.
Highlights
Instead, ~90% of Pancreatic ductal adenocarcinoma (PDAC) cases are diagnosed when the tumors have grown beyond the extent of surgery or metastasized, leaving systemic chemotherapy as the only treatment option
Compared with most other cancer types, PDAC is distinguished by an ultra-low neoplastic cellularity, which accounts for ~10–15% of tumor bulk, and a dense stroma that consists of an acellular extracellular matrix (ECM) infiltrated with CAFs and immune cells [46,47]
Recent work from our lab showed that PDAC cells exposed to FOLFIRINOX markedly upregulate tumor-necrosis factors (TNFs) secretion and autocrine TNFR1 signaling, which drives RIP-dependent cell death programs and transforming growth factor-β-activated kinase 1 (TAK1)-dependent activation of the p38-MK2 kinase cascade
Summary
Clinical trials combining MEK and PI3K/AKT inhibitors have failed to show efficacy and are hindered by significant toxicities [17,18,19,20] These setbacks underscore the critical need to comprehensively re-appraise the breadth of oncogenic feats driven by mutant KRAS for identifying novel therapeutic targets and developing combinatorial strategies that have a higher chance of success in clinical trials. The impact of oncogenic KRAS on the surrounding cell types, fibroblasts, vascular, endothelial, and immune cells, was recently reviewed by Carvalho et al [22], Hamrsheh et al [23], Kitajima et al [24], and Stone et al [25]. We discussed important past and recent clinical trials that target inflammatory pathways in PDAC and provided our perspectives on targeting inflammation in PDAC in future clinical trials
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