Figure 1.

KRAS Oncogene in PDAC and the chemical structure of some of mutant KRAS small molecule inhibitors. (A) Multi-stage development model of KRAS-mutated PDAC. As cells acquire mutations in KRAS, CDKN2A, SMAD4 and TP53 in addition to less commonly mutated genes, the lesion progresses from low grade pancreatic intraepithelial neoplasia (PanIN1), through PanIN2, and high grade PanIN3 to become invasive carcinoma. (B) Most common KRAS mutations in PDAC are G12D (45%), G12V (35%), G12R (17%) representing important targets for PDAC patients. Other mutations such as G12C, G12A and others are less common (3%). (C) Sotorasib and adagrasib are mutant KRAS G12C inhibitors. They bind specifically to the mutant form by making covalent interactions with Cys12 in the switch-II pocket of mutant KRAS, locking it in the inactive state, and preventing downstream signaling. These agents have been investigated in clinical trials, and sotorasib is currently FDA approved for the treatment of KRAS G12C-mutated NSCLC. (D) Novel KRAS G12D inhibitors with available chemical structures, MRTX1133, TH-Z827, TH-Z835, and KD-8. These agents bind specifically and non-covalently to mutant KRAS G12D, thereby inhibiting proliferation in mutated cells. These agents are currently in preclinical development, and details on further clinical development are not currently known.