Inactivation of PRIM1 Function Sensitizes Cancer Cells to ATR and CHK1 Inhibitors

Area of Science:

• Molecular Biology
• Cancer Research
• DNA Damage Response

Background:

• ATR (Ataxia-Telangiectasia and Rad3-related) kinase is crucial for DNA damage response.
• ATR inhibition shows promise in eliminating cancer cells via synthetic lethality with DNA repair genes.
• PRIM1, part of the polymerase α-primase complex, was previously identified as synthetically lethal with ATR.

Purpose of the Study:

• To confirm and mechanistically investigate the synthetic lethality between ATR and PRIM1 in cancer cells.
• To explore the therapeutic potential of targeting PRIM1 in combination with ATR or CHK1 inhibitors.

Main Methods:

• Utilized a genetic ATR knock-in model of colorectal cancer cells.
• Employed siRNA to deplete PRIM1 and assessed cell proliferation.
• Investigated the role of ATR and CHK1 chemical inhibitors in combination with PRIM1 depletion.
• Analyzed cell cycle progression, DNA damage markers, and apoptosis pathways.

Main Results:

• PRIM1 depletion significantly inhibited proliferation in ATR-deficient colorectal cancer cells.
• Combined inhibition of ATR or CHK1 with PRIM1 depletion reduced proliferation across different cell lines.
• PRIM1 depletion in ATR-deficient cells led to S-phase arrest without increased DNA damage, followed by apoptosis.
• Wee1-mediated activation of caspase 8 was identified as a key apoptotic pathway.

Conclusions:

• PRIM1 functions synthetically lethally with ATR deficiency, offering a new therapeutic vulnerability.
• PRIM1 inactivation sensitizes cancer cells to ATR and CHK1 inhibitors.
• Mutations in PRIM1 or the polymerase α-primase complex could be novel targets for individualized cancer therapy using ATR/CHK1 inhibitors.