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Targeted Cancer Therapy: KRAS-Specific Treatments for Pancreatic Cancer

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Handbook of Chemical Biology of Nucleic Acids

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Abstract

Pancreatic cancer is highly dependent on the activity of the KRAS oncogene, which controls the redox homeostasis and induces metabolic reprogramming. Since KRAS is critical for the growth of ~30% of human tumors, targeting this oncogene is a high priority in cancer therapy. Despite its proven importance in cancer, the numerous efforts over the last three decades to develop inhibitors for protein KRAS or for downstream signaling pathways have not reached the clinic. For this reason, the KRAS oncogene has been for a long time considered undruggable. Two sequence elements of KRAS, located in the promoter and 5′-untranslated region (UTR), have high guanine content that allows folding into G-quadruplex (G4) structures. The G4 motif near the transcription initiation site called 32R acts as a hub for transcription factors, making it an attractive target for small molecules capable of competing DNA-protein interactions. In addition, the 5′-UTR of mRNA folds into a complex tertiary structure in which three nonoverlapping G4 motifs near the 5′-cap form RNA G-quadruplexes that are recognized by cationic porphyrins: photosensitizers that, when irradiated, can generate the strong oxidant singlet oxygen 1O2, which degrades mRNA and inhibits translation. In addition, other KRAS targeting mechanisms based on the use of decoy oligonucleotides mimicking the critical promoter G4 structure and miRNA 216b targeting the 3′-UTR sequence are discussed.

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  1. Department of Medicine, Laboratory of Biochemistry, University of Udine, Udine, Italy

    Himanshi Choudhary & Luigi E. Xodo

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  1. Himanshi Choudhary
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  2. Luigi E. Xodo
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Correspondence to Luigi E. Xodo .

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  1. Frontier Institute for Biomolecular Engineering Research (FIBER), Konan University, Kobe, Japan

    Naoki Sugimoto

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  1. Chemistry & Biochemistry, University of Maryland, Baltimore County, Baltimore, USA

    Katherine Seley-Radtke

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Choudhary, H., Xodo, L.E. (2022). Targeted Cancer Therapy: KRAS-Specific Treatments for Pancreatic Cancer. In: Sugimoto, N. (eds) Handbook of Chemical Biology of Nucleic Acids. Springer, Singapore. https://doi.org/10.1007/978-981-16-1313-5_69-1

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  • DOI: https://doi.org/10.1007/978-981-16-1313-5_69-1

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