Combinations of RAS pathway inhibitors with targeted agents are active in spheroids of patient-derived cells with oncogenic KRAS variants from multiple cancer types DOI Creative Commons

Zahra Davoudi,

Thomas S. Dexheimer, Nathan P. Coussens

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 18, 2024

ABSTRACT The KRAS gene is among the most frequently altered genes in cancer and protein was long deemed undruggable. Recent strategies to target oncogenic have included both direct inhibition of indirect its activity by targeting upstream downstream signaling pathway mediators. A high-throughput screen multi-cell type tumor spheroids designed identify active combinations targeted small molecules inhibitors. Inhibitors non-receptor tyrosine phosphatase SHP2 guanine nucleotide exchange factor SOS1 were tested evaluate inhibition, while sotorasib directly inhibited G12C variant. As single agents, inhibitor batoprotafib (TNO155) exhibited selectivity towards with G12C, whereas BI-3406 showed varying across variants. Vertical RAS/MEK/ERK or kinases MEK (trametinib) ERK (temuterkib) highly effective. Inhibition receptor nintedanib combination also effective, sotorasib, demonstrated synergy harboring G12C. Dual PI3K/AKT/mTOR pathways either mTORC1/2 sapanisertib AKT ipatasertib activity, primarily Combination BCL-2 venetoclax resulted additive synergistic cytotoxicity. Lastly, concurrent containing SIGNIFICANCE variants are drivers for a range human cancers. Multiple molecule agents that RAS screened reduced viability spheroid models variety solid tumors. Combinations warranting further testing identified.

Язык: Английский

Novel KRAS Inhibitors for Treating Non-Small-Cell Lung Cancer DOI Creative Commons
Ram W. Sabnis

ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 15(6), С. 773 - 774

Опубликована: Май 22, 2024

Provided herein are novel KRAS inhibitors, pharmaceutical compositions, use of such compounds in treating non-small-cell lung cancer, and processes for preparing compounds.

Язык: Английский

Процитировано

1
Novel KRAS Inhibitors for Treating Non-small Cell Lung Cancer DOI Creative Commons
Ram W. Sabnis

ACS Medicinal Chemistry Letters, Год журнала: 2024, Номер 15(8), С. 1201 - 1202

Опубликована: Июль 25, 2024

Provided herein are novel KRAS inhibitors, pharmaceutical compositions, use of such compounds in treating non-small cell lung cancer, and processes for preparing compounds.

Язык: Английский

Процитировано

0
Combinations of RAS pathway inhibitors with targeted agents are active in spheroids of patient-derived cells with oncogenic KRAS variants from multiple cancer types DOI Creative Commons

Zahra Davoudi,

Thomas S. Dexheimer, Nathan P. Coussens

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 18, 2024

ABSTRACT The KRAS gene is among the most frequently altered genes in cancer and protein was long deemed undruggable. Recent strategies to target oncogenic have included both direct inhibition of indirect its activity by targeting upstream downstream signaling pathway mediators. A high-throughput screen multi-cell type tumor spheroids designed identify active combinations targeted small molecules inhibitors. Inhibitors non-receptor tyrosine phosphatase SHP2 guanine nucleotide exchange factor SOS1 were tested evaluate inhibition, while sotorasib directly inhibited G12C variant. As single agents, inhibitor batoprotafib (TNO155) exhibited selectivity towards with G12C, whereas BI-3406 showed varying across variants. Vertical RAS/MEK/ERK or kinases MEK (trametinib) ERK (temuterkib) highly effective. Inhibition receptor nintedanib combination also effective, sotorasib, demonstrated synergy harboring G12C. Dual PI3K/AKT/mTOR pathways either mTORC1/2 sapanisertib AKT ipatasertib activity, primarily Combination BCL-2 venetoclax resulted additive synergistic cytotoxicity. Lastly, concurrent containing SIGNIFICANCE variants are drivers for a range human cancers. Multiple molecule agents that RAS screened reduced viability spheroid models variety solid tumors. Combinations warranting further testing identified.

Язык: Английский

Процитировано

0