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Targeting human gastrointestinal stromal tumor cells with a quadruplex-binding small molecule
Mekala Gunaratnam1, Stephen Swank, Shozeb M Haider
1CRUK Biomolecular Structure Group, School of Pharmacy, University of London, London, WC1N 1AX, U.K.
Abstract:
Most of human gastrointestinal stromal tumors (GIST) are driven by activating mutations in the proto-oncogene KIT, a tyrosine kinase receptor. Clinical treatment with imatinib targets the kinase domain of KIT, but tumor regrowth occurs as a result of the development of resistant mutations in the kinase active site. An alternative small-molecule approach to GIST therapy is described, in which the KIT gene is directly targeted, and thus, kinase resistance may be circumvented. A naphthalene diimide derivative has been used to demonstrate the concept of dual quadruplex targeting. This compound strongly stabilizes both telomeric quadruplex DNA and quadruplex sites in the KIT promoter in vitro. It is shown here that the compound is a potent inducer of growth arrest in a patient-derived GIST cell line at a concentration (approximately 1 microM) that also results in effective inhibition of telomerase activity and almost complete suppression of KIT mRNA and KIT protein expression. Molecular modeling studies with a telomeric quadruplex have been used to rationalize aspects of the experimental quadruplex melting data.
Insights
This study introduces a novel small molecule that targets the KIT gene directly, circumventing imatinib resistance in gastrointestinal stromal tumors (GIST). The compound effectively halts GIST cell growth by inhibiting KIT expression and telomerase activity.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Gastrointestinal stromal tumors (GIST) are often driven by KIT proto-oncogene mutations.
- Imatinib therapy targets KIT kinase but faces resistance due to secondary mutations.
- Alternative therapeutic strategies are needed to overcome imatinib resistance in GIST.
Purpose of the Study:
- To explore a novel small-molecule approach targeting the KIT gene directly in GIST.
- To investigate the potential of dual quadruplex targeting to circumvent kinase resistance.
- To evaluate a naphthalene diimide derivative for GIST treatment.
Main Methods:
- Utilized a naphthalene diimide derivative for dual quadruplex DNA targeting.
- Assessed compound efficacy in a patient-derived GIST cell line.
- Measured growth arrest, telomerase activity, KIT mRNA, and protein expression.
- Employed molecular modeling to analyze quadruplex interactions.
Main Results:
- The compound stabilized telomeric and KIT promoter quadruplex DNA in vitro.
- Demonstrated potent GIST cell growth arrest at approximately 1 microM concentration.
- Showed effective inhibition of telomerase activity.
- Achieved near-complete suppression of KIT mRNA and protein expression.
Conclusions:
- Dual quadruplex targeting offers a promising strategy for GIST therapy.
- The studied naphthalene diimide derivative effectively inhibits GIST progression by targeting the KIT gene.
- This approach may overcome resistance mechanisms associated with conventional KIT inhibitors.
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