Key Points
• In the current review, authors examined current trends in targeting KRAS mutations, including the current challenges and future directions of KRAS inhibitors.
• They acknowledged that current agents targeting the KRAS G12C mutation are a breakthrough, however this is unlikely in solid tumors other than lung adenocarcinoma—including pancreatic ductal adenocarcinoma and colorectal cancer.
• To potentiate the effect of KRAS G12C inhibitors, the authors suggested various combination therapies with “immune checkpoint inhibitors and inhibitors of RAS related pathways, including insulin-like growth factor (IGF)1 and mTOR, and receptor tyrosine kinases and PI3K, are currently under investigation [91]. Pan KRAS inhibitors, including drugs targeting son of sevenless 1 (SOS1) and SHP2, are in early phases of clinical development, either as monotherapies or in combination with MEK inhibitors (Table 1). Another promising strategy includes targeting the transcription initiation factor 4 (eIF4), which is part of an essential protein complex regulating the translation initiation of multiple oncogenic pathways, including KRAS.”
• They also discussed the use of proteolysis-targeted chimeras (PROTACs), which trigger the selective degradation of the target protein of interest such as KRAS G12C. PROTACs lead to the ubiquitination and subsequent proteasomal degradation of KRAS G12C, for example.
• They stressed a synergistic relationship between KRAS inhibitors and immune checkpoint inhibitors, as well as mRNA-based vaccines and adoptive T cell therapy specifically targeting KRAS G12 D/V,