Could Drug Delivery Systems Be Enhancers for Therapy against KRAS-driven Cancers?

KRAS (Kirsten rat sarcoma viral oncogene homologue) is the most frequently mutated gene in the RAS superfamily, involved in up to 85% of all RAS-driven cancers according to various databases. KRAS mutations are associated with up to 98% of pancreatic, 50% of colorectal, and 30% of lung cancers. The KRAS gene encodes the eponymous p21 small GTP-binding protein, which functions as a binary switch (On/Off) and plays a crucial role in signaling pathways that regulate cell proliferation, growth, differentiation, migration, and survival through several downstream pathways. Hyperactivation of KRAS protein signaling as a result of direct gene mutation significantly contributes to tumorigenesis, making KRAS a “holy grail” in cancer drug discovery. Despite intense research efforts, KRAS has long been considered “undruggable” due to its smooth surface and high affinity for GTP/GDP binding. However, the past decade has seen the discovery of inhibitors that specifically target KRAS. These inhibitors bind irreversibly to the Cys12 residue, making them specific for cancers with KRASG12C mutations. Emerging resistance and the ability to bind only to the GDP-bound form have quickly become restricting factors. Meanwhile, not all cancers are related to KRASG12C; mutations also occur at codons 13, 61, and 146, with different amino acid changes. Although inhibitors targeting these mutations are under development, their success is also not guaranteed. The 40-year history of attempts to treat KRAS has led to indirect strategies, such as pan-RAS inhibitors, that inhibit KRAS-mediated signal transmission, RNA-based approaches to reduce KRAS expression, and combination therapies targeting upstream and downstream pathways. Nanomedicine may provide additional access to anti-KRAS therapy. This review focuses on drug delivery system approaches to treating KRAS-driven cancers. It discusses recent advances in the development of vehicles for the delivery of direct KRAS inhibitors, nucleic acid-based therapies, anti-KRAS vaccines, RAS-specific proteases, intracellular KRAS-targeting antibodies, and combinations with p53 inhibitors, tyrosine kinase receptor inhibitors, and chemotherapeutic agents. Additionally, it explores the potential of nanomedicine to improve drug delivery to pancreatic and lung cancers with KRAS mutations.