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Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors - PubMed

Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors - PubMed

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https://pubmed.ncbi.nlm.nih.gov/34064352/

Activating mutations in RAS family proteins are found in ~25% of all human cancers. Different solid tumors are correlated with mutations in certain isoforms of RAS, with Kirsten RAS (KRAS) being the most frequently mutated isoform. Historically, KRAS has been acknowledged as "undruggable", largely b ...

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    Key Points
    • In the current review, authors examined the role of the KRAS mutation in different solid tumors, as well as examining KRAS inhibitors that have come to the fore.
    • The authors noted that sotorasib and adagrasib, which target KRAS G12C inhibition, are the most promising drugs targeting KRAS to date. Nevertheless, KRAS G12C mutation is detected in only a small number of those with KRAS mutation, and, in preclinical studies, several mechanisms of acquired resistance to KRAS G12C exist, thus triggering alternative RAS dependent pathways,
    • The authors wrote, “In order to maximize the effect of these inhibitors, several 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. 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. 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. “