A high-throughput screen identifies that CDK7 activates glucose consumption in lung cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Elevated glucose consumption is a hallmark of cancer, presenting a challenge for targeted therapies.
• Selective inhibition of cancer glucose metabolism requires novel screening methods and molecular targets.

Purpose of the Study:

• To develop a high-throughput assay for screening glucose consumption inhibitors in non-small-cell lung cancer (NSCLC).
• To identify novel small molecules that selectively target glucose metabolism in NSCLC.
• To elucidate the molecular mechanisms by which identified compounds regulate glucose consumption.

Main Methods:

• Development of a high-throughput assay to measure glucose consumption.
• Screening of NSCLC cell lines against a library of bioactive small molecules.
• Analysis of gene and protein expression (SLC2A1/GLUT1), glucose transport inhibition, and kinase activity (CDK7).
• Investigation of the role of PI3K/AKT pathway signaling and RNA Polymerase II phosphorylation.

Main Results:

• Identification of Milciclib as a compound that inhibits glucose consumption in H460 and H1975 NSCLC cells.
• Milciclib reduces SLC2A1 (GLUT1) mRNA and protein levels, inhibiting glucose transport.
• Milciclib targets cyclin-dependent kinase 7 (CDK7), similar to THZ1 and LDC4297.
• CDK7 inhibition reduces RNA Polymerase II phosphorylation on the SLC2A1 promoter, particularly in cells with enhanced PIK3CA signaling.

Conclusions:

• The developed high-throughput assay effectively identifies compounds regulating cancer glucose consumption.
• CDK7 is a critical regulator of glucose consumption, especially in cancer cells with activated PI3K pathway signaling.
• Milciclib and other CDK7 inhibitors represent potential therapeutic agents for specific NSCLC subtypes.