High-throughput screening identifies NT-1 that synergizes with MRTX1133 against acquired resistant KRASG12D colorectal cancer

Metastatic colorectal cancer (mCRC) remains a significant clinical challenge, with a 5-year survival rate of 10%. Approximately 40% of CRCs harbor mutations in the KRAS gene, leading to poor response to standard therapy. This underscores the crucial need for novel therapeutics targeting KRAS and overcoming the growing barrier of resistance. To address these critical challenges, we conducted a high-throughput screen to identify small molecules that synergize with the KRASG12D inhibitor MRTX1133 against CRC. Through screening a 2,652-kinase inhibitor library, we discovered that Osimertinib, an EGFR tyrosine kinase inhibitor, and its analogs strongly synergize with MRTX1133 against both parental and MRTX1133-resistant cells. The top compound from the screen, NT-1, is a chemical analog of Osimertinib. NT-1 strongly synergized with MRTX1133 to suppress EGFR/MAPK signaling and induce apoptosis in an MRTX1133-resistant patient-derived organoid model of CRC. We present novel small molecule combinations with the potential to overcome the limitations of KRAS inhibitors with direct clinical translational applications.