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.
Highlights
Accepted: 20 September 2021Mutations in the RAS gene family are common in many cancer types
The point mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene typically affect the hotspots at codons 12 and 13 [1,2] at lower frequencies, KRAS mutations can occur in codons 18, 61, 117, and 146
KRAS mutations are predominant in most cancers, such as pancreatic ductal adenocarcinoma (PDAC) (86%), colorectal cancer (CRC) (85%), and lung cancer (30%) [3]
Summary
Mutations in the RAS gene family are common in many cancer types. The point mutations in the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene typically affect the hotspots at codons 12 and 13 [1,2] at lower frequencies, KRAS mutations can occur in codons 18, 61, 117, and 146. KRAS mutations are predominant in most cancers, such as pancreatic ductal adenocarcinoma (PDAC) (86%), colorectal cancer (CRC) (85%), and lung cancer (30%) [3]. This is followed by NRAS (12%) mutations, which are predominant in cutaneous melanoma and acute myelogenous leukemia. The significance of KRAS mutations in PDAC will be discussed. We will highlight the link between diabetes and PDAC, as well as the importance of vitamin D for effective targeted therapies
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