Reflections on drug resistance to KRAS(G12C)( )inhibitors and gene silencing/editing tools for targeting mutant KRAS in cancer treatment

KRAS is the most commonly mutated oncogene in human tumors, especially in lung, pancreatic, and colorectal cancers. Small-molecule inhibitors targeting mutant KRAS(G12C) demonstrated promising anti-tumor effect in patients with non-small cell lung cancer harboring KRAS(G12C) mutation, while the intrinsic and acquired drug resistance occurred frequently and might be inevitable. Unlike the protein-level inhibition approach, gene silencing/editing tools for DNA-level knockout and RNA-level knockdown of mutant KRAS may be advantageous since these approaches directly eliminate the production of mutant KRAS-encoded protein. An in-depth understanding of KRAS biology, drug resistance to KRAS(G12C) inhibitors and gene silencing/editing methods applied for anti-KRAS therapy may give new insight into the therapeutic strategy for cancer treatment.