KRAS G12D targeted therapies for pancreatic cancer: Has the fortress been conquered?

Abstract

KRAS mutations are among the most commonly occurring mutations in cancer. After being deemed undruggable for decades, KRAS G12C specific inhibitors showed that small molecule inhibitors can be developed against this notorious target. At the same time, there is still no agent that could target KRAS G12D which is the most common KRAS mutation and is found in the majority of KRAS-mutated pancreatic tumors. Nevertheless, significant progress is now being made in the G12D space with the development of several compounds that can bind to and inhibit KRAS G12D, most notably MRTX1133. Exciting advances in this field also include an immunotherapeutic approach that uses adoptive T-cell transfer to specifically target G12D in pancreatic cancer. In this mini-review, we discuss recent advances in KRAS G12D targeting and the potential for further clinical development of the various approaches.