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Biochemical pharmacology

Biochemical pharmacology

IF: 5.3
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Basroparib overcomes acquired resistance to MEK inhibitors by inhibiting Wnt-mediated cancer stemness in KRAS-mutated colorectal cancer

Published:28 February 2025 DOI: 10.1016/j.bcp.2025.116842 PMID: 40024348
Young-Ju Kwon , Dong Young Kim , Uk-Il Kim , Song Hyun Kim , Ye-hyun Kim , Kyungjin Kim , Jae-Sung Kim

Abstract

Mitogen-activated protein kinase (MEK) inhibitors show promise in treating KRAS-mutated cancers, including colorectal cancer (CRC). However, acquired resistance to MEK inhibitors often results in failure of effective treatment in patients with KRAS-mutated CRC. Here, we demonstrated that basroparib overcomes MEK inhibitor resistance in KRAS-G12V- or -G12D-mutated CRC. This basroparib-mediated sensitization was dependent on the KRAS mutation status and was enhanced specifically in KRAS-G12V- or -G12D-mutated cells. Additionally, when combined with MEK inhibitors, basroparib significantly reduced tumor growth in KRAS-G12V-mutated CRC xenograft models, but not in KRAS-G13D-mutated and -wild-type models. Furthermore, basroparib sensitized KRAS-G12V-mutated CRC cells with acquired resistance to MEK inhibitors. Notably, when combined with MEK inhibitors, basroparib not only suppressed tumor regrowth but also prolonged the survival of tumor models with acquired resistance to MEK inhibitors. Mechanistically, basroparib suppressed Wnt-mediated cancer stemness, a bypass mechanism for acquired resistance to MEK inhibitors in KRAS-mutated CRC. This study provides the first preclinical evidence of the relevance of basroparib in treating CRC with acquired resistance to MEK inhibitors due to APC and KRAS mutations, possibly by reducing the Wnt-mediated cancer stemness.

Substances (10)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Trametinib 871700-17-3 C26H23FIN5O4 386 suppliers $28.00-$4391.10
Trametinib 871700-17-3 C26H23FIN5O4 386 suppliers $28.00-$4391.10
Trametinib 871700-17-3 C26H23FIN5O4 386 suppliers $28.00-$4391.10
Trametinib 871700-17-3 C26H23FIN5O4 386 suppliers $28.00-$4391.10
Trametinib 871700-17-3 - Inquiry
Trametinib 871700-17-3 - Inquiry
Trametinib 871700-17-3 - Inquiry
Trametinib 871700-17-3 - Inquiry
871700-17-3 871700-17-3 - Inquiry
871700-17-3 871700-17-3 - Inquiry

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