High-throughput screening identifies NT-1 that synergizes with MRTX1133 against acquired resistant KRASG12D colorectal cancer
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Updated: Apr 10, 2026
A Multiplexed Luciferase-based Screening Platform for Interrogating Cancer-associated Signal Transduction in Cultured Cells
Published on: July 3, 2013
Natalie Thielen1,2,3, Ning Wei4,5,6, Emiko Nagai1,3
1Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, New York, NY, USA.
Abstract:
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.
Insights
New drug combinations show promise for treating metastatic colorectal cancer (mCRC). Osimertinib analogs synergize with KRAS inhibitors to overcome treatment resistance, offering potential new therapies for KRAS-mutated colorectal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Metastatic colorectal cancer (mCRC) presents a significant clinical challenge with a low 5-year survival rate.
- KRAS mutations, found in ~40% of CRCs, confer resistance to standard therapies.
- Targeting KRAS and overcoming resistance are critical needs for effective mCRC treatment.
Purpose of the Study:
- To identify small molecules that synergize with the KRASG12D inhibitor MRTX1133.
- To discover novel therapeutic strategies for KRAS-mutated colorectal cancer (CRC).
- To overcome resistance mechanisms associated with KRAS-targeted therapies.
Main Methods:
- High-throughput screening of a 2,652-kinase inhibitor library.
- Evaluation of drug synergy between MRTX1133 and identified compounds in CRC models.
- Assessment of signaling pathway inhibition (EGFR/MAPK) and apoptosis induction.
Main Results:
- Osimertinib and its analogs demonstrated strong synergy with MRTX1133 against both parental and resistant CRC cells.
- NT-1, an Osimertinib analog, synergized with MRTX1133 to suppress EGFR/MAPK signaling.
- NT-1 and MRTX1133 combination induced apoptosis in an MRTX1133-resistant patient-derived organoid model.
Conclusions:
- Novel small molecule combinations, including Osimertinib analogs and MRTX1133, can overcome KRAS inhibitor resistance in CRC.
- These combinations effectively suppress oncogenic signaling and induce cancer cell death.
- The findings have direct clinical translational potential for treating KRAS-mutated mCRC.
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