Targeting KRAS in pancreatic cancer: new drugs on the horizon

Abstract

Kirsten Rat Sarcoma (KRAS) is a master oncogene involved in cellular proliferation and survival and is the most commonly mutated oncogene in all cancers. Activating KRAS mutations are present in over 90% of pancreatic ductal adenocarcinoma (PDAC) cases and are implicated in tumor initiation and progression. Although KRAS is a critical oncogene, and therefore an important therapeutic target, its therapeutic inhibition has been very challenging, and only recently specific mutant KRAS inhibitors have been discovered. In this review, we discuss the activation of KRAS signaling and the role of mutant KRAS in PDAC development. KRAS has long been considered undruggable, and many drug discovery efforts which focused on indirect targeting have been unsuccessful. We discuss the various efforts for therapeutic targeting of KRAS. Further, we explore the reasons behind these obstacles, novel successful approaches to target mutant KRAS including G12C mutation as well as the mechanisms of resistance.

Keywords: KRAS; KRAS inhibitor; KRAS vaccine; KRASG12C; KRASG12C inhibitors; PROTACs; Pancreatic cancer.

Fig. 1. Schematic illustration of KRAS pathway and targeted preclinical and clinical agents.

Receptors in the EGFR family upstream of KRAS transmit extracellular signals to activate KRAS. KRAS is activated via GDP to GTP exchange catalyzed by GEFs such as SOS, whereas GAPs catalyze the GTPase activity of KRAS. Downstream signaling pathways include the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, which result in the expression of genes that promote survival, growth, and metastasis. Inhibitors or other targeted agents in the upstream or downstream of KRAS signaling have been depicted. RASGAPs RAS GTPase activating proteins, RASGEFs RAS guanine exchange factors, CRBN cereblon, PROTACs proteolysis targeting chimeras, VHL Von Hippel–Lindau tumor suppressor

Fig. 2. Various novel approaches to target mutant KRAS.

Basic concepts of targeting mutated KRAS using tricomplex inhibitors, PROTACs, and mRNA vaccine have been illustrated in the figure. Tricomplex inhibitors utilize an endogenous chaperone protein to create a novel pocket for small molecule KRAS inhibitors. PROTACs recruit an endogenous E3 Ligase to mutant KRAS, thus targeting it for proteasomal-mediated degradation. mRNA vaccines utilize the mRNA code of mutant KRAS, encapsulated in a lipid nanoparticle to stimulate the immune response against tumor-associated neoantigens. mKRASi mutant KRAS inhibitor, PROTACs proteolysis targeting chimeras, VHL Von Hippel–Lindau tumor suppressor