Related Experiment Video
Updated: Apr 14, 2026
Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC Crosslinking of Small Molecules to Isolate Chromatin
Published on: January 20, 2016
Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole-imidazole polyamide conjugate
Kiriko Hiraoka1, Takahiro Inoue1, Rhys Dylan Taylor2
1Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuoh-ku, Chiba 260-8717, Japan.
Abstract:
Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis. In xenograft models, KR12 infusions induce significant tumour growth suppression, with low host toxicity in KRAS-mutated but not wild-type tumours. This newly developed approach may be applicable to the targeting of other mutant driver oncogenes in human tumours.
Insights
Researchers developed KR12, a novel agent that directly targets KRAS mutant DNA. This breakthrough selectively kills cancer cells with KRAS mutations, offering a promising new avenue for cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Targeting mutated RAS proteins, particularly KRAS, remains a significant challenge in cancer therapy.
- Existing anticancer agents lack selectivity for tumor cells with specific KRAS mutations.
Purpose of the Study:
- To develop a novel synthetic agent for direct targeting of oncogenic KRAS mutations.
- To evaluate the efficacy and safety of this agent in preclinical cancer models.
Main Methods:
- Development of a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12).
- Demonstration of KR12's selective recognition of codon 12 KRAS mutations.
- Assessment of KR12's mechanism of action, including DNA alkylation and strand cleavage.
- Evaluation of KR12's anti-tumor effects in human colon cancer cells and xenograft models.
Main Results:
- KR12 selectively targets and alkylates adenine N3 at oncogenic codon 12 KRAS mutation sites.
- KR12 induces DNA strand cleavage, leading to growth suppression, senescence, and apoptosis in KRAS-mutated cancer cells (G12D/G12V).
- KR12 demonstrates significant tumor growth suppression in xenograft models with KRAS mutations, showing low host toxicity.
- No significant toxicity observed in tumors with wild-type KRAS.
Conclusions:
- Direct targeting of KRAS mutant DNA with KR12 is a viable strategy for cancer therapy.
- KR12 exhibits potent anti-tumor activity and selectivity against KRAS-mutated cancers.
- This approach holds potential for broader application in targeting other mutant driver oncogenes.
More Related Videos
06:51Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
Published on: July 21, 2018
12:40A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
