RAS-targeted therapies for pancreatic cancer

Pancreatic adenocarcinoma (PDAC) is a RAS-driven cancer with poor prognosis. Although tremendous progress has been made in other cancers with the development of targeted therapies and immunotherapy, cytotoxic chemotherapy remains the mainstay of treatment for PDAC. For decades, the therapeutic development of RAS-targeted therapy stagnated due to the lack of an identifiable binding pocket. However, the recent breakthrough discovery of the switch-II pocket enabled the development of KRAS^G12C inhibitors, which have demonstrated effective tumor control in many cancers carrying this mutation, including PDAC. Furthermore, a recent clinical trial evaluating the pan-RAS inhibitor, daraxonrasib, demonstrated a survival extension more than double that of conventional chemotherapy in previously treated metastatic PDAC. These encouraging results mark a new dawn of hope for PDAC management. In this review, we provide an updated overview of the therapeutic landscape of RAS inhibitors in PDAC and discuss the future challenges associated with these novel treatments.