Recent Anti-KRASG12D Therapies: A “Possible Impossibility” for Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer, able to thrive in a challenging tumor microenvironment. Current standard therapies, including surgery, radiation, chemotherapy, and chemoradiation, have shown a dismal survival prognosis, resulting in less than a year of life in the metastatic setting. The pressing need to find better therapeutic methods brought about the discovery of new targeted therapies against the infamous KRAS mutations, the major oncological drivers of PDAC. The most common KRAS mutation is KRASG12D, which causes a conformational change in the protein that constitutively activates downstream signaling pathways driving cancer hallmarks. Novel anti-KRASG12D therapies have been developed for solid-organ tumors, including small compounds, pan-RAS inhibitors, protease inhibitors, chimeric T-cell receptors, and therapeutic vaccines. This comprehensive review summarizes the current knowledge on the biology of KRAS-driven PDAC, the latest therapeutic options that have been experimentally validated, and developments in ongoing clinical trials.