Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/219122
Title: α4-α5 helices on surface of KRAS can accommodate small compounds that increase KRAS signaling while inducing CRC cell death
Author: Abuasaker, Baraa
Garrido, Eduardo
Vilaplana, Marta
Gómez Zepeda, Jesús Daniel
Brun, Sonia
Garcia Cajide, Marta
Mauvezin, Caroline
Jaumot i Pijoan, Montserrat
Pujol, Maria Dolors
Rubio Martínez, Jaime
Agell i Jané, Neus
Keywords: Tumors
Genètica
Mutació (Biologia)
Càncer colorectal
Tumors
Genetics
Mutation (Biology)
Colorectal cancer
Issue Date: 1-Jan-2023
Publisher: MDPI
Abstract: Abstract: KRAS is the most frequently mutated oncogene associated with the genesis and progress of pancreatic, lung and colorectal (CRC) tumors. KRAS has always been considered as a therapeutic target in cancer but until now only two compounds that inhibit one specific KRAS mutation have been approved for clinical use. In this work, by molecular dynamics and a docking process, we describe a new compound (P14B) that stably binds to a druggable pocket near the 4- 5 helices of the allosteric domain of KRAS. This region had previously been identified as the binding site for calmodulin (CaM). Using surface plasmon resonance and pulldown analyses, we prove that P14B binds directly to oncogenic KRAS thus competing with CaM. Interestingly, P14B favors oncogenic KRAS interaction with BRAF and phosphorylated C-RAF, and increases downstream Ras signaling in CRC cells expressing oncogenic KRAS. The viability of these cells, but not that of the normal cells, is impaired by P14B treatment. These data support the significance of the 4- 5 helices region of KRAS in the regulation of oncogenic KRAS signaling, and demonstrate that drugs interacting with this site may destine CRC cells to death by increasing oncogenic KRAS downstream signaling. Keywords: colorectal cancer; KRAS; molecular dynamics; docking; allosteric pocket; calmodulin; small molecule inhibitors; RAF; ERK; AKT
Note: Reproducció del document publicat a: https://doi.org/10.3390/ijms24010748
It is part of: International Journal of Molecular Sciences, 2023, vol. 24, num.1, p. 748
URI: https://hdl.handle.net/2445/219122
Related resource: https://doi.org/10.3390/ijms24010748
ISSN: 1661-6596
Appears in Collections:Articles publicats en revistes (Biomedicina)

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