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

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 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.

Language: Английский

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

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(6), P. 773 - 774

Published: May 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.

Language: Английский

Citations

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

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 15(8), P. 1201 - 1202

Published: July 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.

Language: Английский

Citations

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

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 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.

Language: Английский

Citations

0