Oncogenic KRAS-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities

Abstract

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.

Keywords: IRAK4; MK2; TAK1; TPL2; inflammation; pancreatic cancer; stroma.

Figure 1

Overview of the bi-directional onco-inflammatory network between PDAC cells and surrounding cells. Oncogenic KRAS signaling in transformed PDAC cells drives effector cascades leading to secretion of inflammatory cytokines/chemokines such as IL-1α/β, IL-6, and CXCL1 to the TME. These secreted factors not only have autocrine signaling functions but also have paracrine effects by recruiting and reprogramming the surrounding non-neoplastic cells, causing them to secrete more cytokines/chemokines into the TME. These cytokines/chemokines provide additional signaling feedback to PDAC cells through multiple receptors including the TIR (Toll-like/IL-1) receptors, TNF, TGF-β, and Interleukin receptors (IL-6R being the best studied). These receptors utilize overlapping and distinct signal transduction mechanisms to affect cellular outcome, which include production of more cytokines/chemokines, proliferation, survival, migration, autophagy, and resistance to chemotherapy and immune surveillance.

Figure 2

Overview of major inflammatory receptors and the associated signaling network in PDAC cells. Oncogenic KRAS in transformed PDAC cells drives secretion of inflammatory cytokines/chemokines such as IL-1α/β, IL-6, and CXCL1 that subvert other cell types in the TME, causing production of more cytokines and chemokines in the TME. These secreted factors engage with inflammatory receptors on PDAC cells, driving a network of signaling pathways that synergize with oncogenic KRAS signaling in propelling various malignant feats of PDAC.