ReviewExploration of targeted anti-tumor therapy2023
Integration of signaling pathway and bromodomain and extra-terminal domain inhibition for the treatment of mutant Kirsten rat sarcoma viral oncogene homolog cancer.
Review in Exploration of targeted anti-tumor therapy, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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0 citing papers in PubMed, 2 citations in OpenAlex.
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3 authors at 1 institution in 2 countries.
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Abstract
Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) is now a drugable oncogenic driver and the KRAS G12C variant responds clinically to sotorasib and adagrasib that covalently block the cysteine of the active center and inhibit downstream signaling and proliferation. Unfortunately, progression-free survival (PFS) of lung cancer patients is only 5-6 months and no survival advantage has been found for sotorasib in comparison to docetaxel chemotherapy. Increased responses to KRAS inhibitors are tested in combination with the son of sevenless 1 (SOS1) inhibitors, upstream and downstream signaling modulators as well as chemotherapeutics. Some of these approaches are limited by toxicity to normal tissues and by diverse mechanisms of resistance. In essence, most of these attempts are directed to the inhibition of proliferation by impairment of the signal transduction pathways. The final target of KRAS-mediated growth stimulation is MYC in the cell nucleus that stimulates transcription of a host of genes. In detail, MYC alters genomic enhancer and super-enhancers of transcription that are frequently deregulated in cancer. Such enhancers can be targeted by bromodomain and extra-terminal (BET) inhibitors (BETi) or degraders and this review discusses whether integrated SOS1 inhibition and BET targeting of MYC synergizes against mutant KRAS tumor growth. BET degraders in the form of proteolysis-targeting chimeras (PROTACs) combined with BAY-293-mediated SOS1 inhibition revealed marked cytotoxic synergy against mutant KRAS cancer cells and may constitute a promising option for clinical treatment.
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