Abstract
Pancreatic cancer is one of the deadliest human malignancies and little progress has been achieved in its treatment over the past decades. Advances in our understanding of the biology of this disease provide new potential opportunities for treatment. Pancreatic cancer is preceded by precursor lesions, the most common of which are known as Pancreatic Intraepithelial Neoplasia (PanIN). PanIN lesions, which are the focus of this review, have a high incidence of Kras mutations, and Kras mutations are a hallmark of the late-stage disease. We now know from genetically engineered mouse models that oncogenic Kras is not only driving the formation of pancreatic cancer precursor lesions, but it is also required for their progression, and for the maintenance of invasive and metastatic disease. Thus, an enormous effort is being placed in generating Kras inhibitors for clinical use. Additionally, alternative approaches, including understanding the role of Kras effector pathways at different stages of the disease progression, are being devised to target Kras effector pathways therapeutically. In particular, efforts have focused on the MAPK pathway and the PI3K pathway, for which inhibitors are widely available. Finally, recent studies have highlighted the need for oncogenic Kras to establish feedback mechanisms that maintain its levels of activity; the latter might constitute alternative ways to target Kras in pancreatic cancer. Here, we will review recent basic research and discuss potential therapeutic applications.
Highlights
KRAS IN PANCREATIC CANCER INITIATION AND MAINTENANCE The association of mutant Kras with pancreatic cancer was established decades ago (Almoguera et al, 1988; Smit et al, 1988); the most common mutation is one amino-acid substitution in position 12 of the Kras protein, leading to a glycine (G) to aspartic acid (D) substitution, other variants, such as G to V are common
PANCREATITIS AND ONCOGENIC KRAS The observation that Kras mutations occur at much higher frequency than pancreatic cancer in humans is recapitulated in mouse studies, where— every single pancreatic epithelial cell expresses mutant Kras from the early pancreas development—Pancreatic Intraepithelial Neoplasia (PanIN) lesions occur sporadically and only several weeks after birth
It is possible that even low, subclinical levels of local or systemic inflammation might promote the formation of PanINs, in presence of mutant Kras
Summary
Reviewed by: Kennichi Satoh, Miyagi Cancer Research Institute, Japan Dieter Saur, Technische Universität München, Germany Windel E. Recent tumor genome sequencing studies have established the prevalence of mutant Kras in Pancreatic Intraepithelial Neoplasia (PanINs), the most common precursor lesions (Kanda et al, 2012), and in pancreatic cancer (Jones et al, 2008; Biankin et al, 2012) with increased precision. Results from these studies confirm the notion that over 90% of early stage PanIN and invasive tumors express mutant Kras.
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