Colorectal cancer (CRC) harboring the KRAS G12D mutation remains a formidable therapeutic challenge, especially when tumors develop resistance to targeted inhibition. In this study, we performed a high-throughput screen of 2,652 kinase inhibitors to identify compounds that synergize with the KRAS G12D inhibitor MRTX1133 in both parental and MRTX1133-resistant CRC cell lines. The screening revealed that analogs of Osimertinib, including a lead compound termed NT-1, significantly potentiated the effect of MRTX1133 by suppressing EGFR/MAPK signalling and inducing apoptosis in resistant patient-derived organoid (PDO) models. Mechanistically, the combination’s efficacy appears to stem from dual targeting of oncogenic transcriptional and signalling dependencies, thereby circumventing the survival pathways leveraged by resistant cells. Importantly, the identification of clinically relevant small molecules that augment KRAS G12D inhibition opens a translational path: these combination strategies could move toward early-phase clinical testing in KRAS-mutant CRC. Our work exemplifies how systematic drug screening integrated with PDO models can yield actionable therapeutic opportunities to tackle resistance in precision oncology.
Combating KRAS G12D Resistance in Colorectal Cancer: Discovery of Synergistic Drug Combinations
Description
Far far away, behind the word mountains, far from the countries Vokalia and Consonantia, there live the blind texts. Separated they live in Bookmarksgrove right at the coast.
When
January 2017
Who
Jason Davis, John Anderson, Mirco Cattabriga, Aaron Jones, Amanda Johnson, Steve McQueen
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