Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma

Abstract

The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.

KRAS Mutations in Solid Tumors: Characteristics, Current Therapeutic Strategy, and Potential Treatment Exploration

“…With the application of monoclonal antibodies targeting programmed death 1 (PD-1) and its primary ligand PD-L1, the treatment paradigm for most advanced solid tumors has been fundamentally altered. Further studies have also been conducted in KRAS mutant tumors, and data shows that KRAS mutations may reshape the tumor immune microenvironment [ 62 ]. An analyzer powered by artificial intelligence based on hematoxylin and eosin showed that KRAS mutations were mostly found in the inflamed subtype of the immune microenvironment [ 63 ].…”

Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study

“… 25 Activating KRAS mutations are the earliest and most common genetic alterations to occur in PDAC progression; they are present in greater than 90% of low‐grade PanINs and 90–95% of PDAC. 26 , 27 , 28 KRAS encodes a membrane‐bound GTPase that regulates a range of critical intracellular processes such as cell growth, differentiation, and survival by moving between its GDP‐bound inactive and GTP‐bound active form. 25 , 29 KRAS is usually present in quiescent cells in its inactive form; upon growth stimulation, guanine nucleotide exchange factors (GEFs) catalyze the GDP–GTP exchange to change KRAS into its active state.…”

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression

“…This can result in the differentiation of CD4 + CD25 − cells into T regulatory (Treg) cells [ 7 ] and recruitment in colorectal cancer (CRC), PDAC and other cancers [ 8 ]. In addition, KRAS mutations induce growth factors such as interleukin-6 (IL-6) and IL-10, transforming growth factor-β (TGF-β) and sonic hedgehog (Shh) [ 9 ].…”