by Claudia Casal Montserrat
Games Editor
The Food and Drug Administration (FDA) granted approval of daraxonrasib, a Rat sarcoma (RAS) inhibitor for metastatic pancreatic cancer, on Aug. 26. RAS, a GTPase protein, has been notoriously difficult to inhibit and had extremely good results in clinical trials.
Non-mutant RAS is like a cellular on-and-off switch for growing and dividing. When it is activated by a growth factor, it initiates several pathways, telling the cell to grow, divide, and differentiate. When RAS is mutated, it is no longer controlled by the growth factor and permanently stuck in the “on” state, leading to unregulated cell growth that causes tumors and various types of cancers. Thus, RAS mutations are a leading cause of pancreatic, colorectal, and lung cancers.
RAS proteins have an extremely smooth surface, and lack pockets that drugs conventionally use as binding sites. The only pocket that the protein does have is for guanosine triphosphate (GTP) and guanosine diphosphate (GDP), which is very similar to adenosine triphosphate (ATP), and is a specialized energy carrier. RAS has such a high binding affinity to GTP and GDP that it would be unrealistic to have a drug bind to that site. For these reasons, the RAS proteins were proclaimed as undruggable since their discovery.
Mutations of Kristen Rat sarcoma (KRAS), a type of RAS, are responsible for almost 90% of all pancreatic ductal adenocarcinoma, and have been an even bigger challenge to bind to. Kevin Shokat and his team were able to freeze cells and image KRAS in its “on” state, leading to the discovery of the switch-II pocket that could serve as a drug binding site. Since the increase in imaging of KRAS and other RAS mutations, the once undruggable protein can be inhibited, however, there are still few FDA-approved RAS inhibitors.
Daraxonrasib differs from traditional RAS inhibitors by not targeting the RAS protein. Rather, it binds to the helper protein cyclophilin A. Although cyclophilin A and RAS proteins do not naturally interact in cells, when bound to daraxonrasib, cyclophilin A sticks to the GTP bound state of a RAS protein, not allowing the RAS to interact with other proteins, stopping its effects. This drug treats a wider range of patients as it doesn’t target a specific RAS mutation, but rather, all RAS proteins.
In clinical trials, daraxonrasib has had incredible results. The median of patients survived 13.2 months, compared to the 6.7 months median survival under traditional chemotherapy, nearly doubling the survival of patients. Additionally, 31.6% of patients responded to daraxonrasib, compared to the 11.2% for traditional chemotherapy. However, since the drug targets all types of RAS proteins, even nonmutated types, patients have experienced rashes, mouth sores, and diarrhea. Even so, only 1.2% of patients stopped taking daraxonrasib because of the side effects compared to the 11.2% patients of chemotherapy.
Daraxonsib is the first effective FDA pan-RAS inhibitor, and provides hope for the 65,000 people a year that are diagnosed with metastatic pancreatic ductal adenocarcinoma, which face a five-year 3% survival rate.
(Sources: ACS, JCI, Nature, and New England Journal of Chemistry)