Skip to Content
Merck
  • A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors.

A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors.

Nature cancer (2021-06-29)
Jia Zhou, Camille Gelot, Constantia Pantelidou, Adam Li, Hatice Yücel, Rachel E Davis, Anniina Färkkilä, Bose Kochupurakkal, Aleem Syed, Geoffrey I Shapiro, John A Tainer, Brian S J Blagg, Raphael Ceccaldi, Alan D D'Andrea
ABSTRACT

DNA polymerase theta (POLθ) is synthetic lethal with Homologous Recombination (HR) deficiency and thus a candidate target for HR-deficient cancers. Through high-throughput small molecule screens we identified the antibiotic Novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo. NVB directly binds to the POLθ ATPase domain, inhibits its ATPase activity, and phenocopies POLθ depletion. NVB kills HR-deficient breast and ovarian tumors in GEMM, xenograft and PDX models. Increased POLθ levels predict NVB sensitivity, and BRCA-deficient tumor cells with acquired resistance to PARP inhibitors (PARPi) are sensitive to NVB in vitro and in vivo. Mechanistically, NVB-mediated cell death in PARPi-resistant cells arises from increased double-strand break end resection, leading to accumulation of single-strand DNA intermediates and non-functional RAD51 foci. Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance. (151/150).

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal ANTI-FLAG® M2 antibody produced in mouse, 1 mg/mL, clone M2, affinity isolated antibody, buffered aqueous solution (50% glycerol, 10 mM sodium phosphate, and 150 mM NaCl, pH 7.4)
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Anti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301, clone JBW301, Upstate®, from mouse
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Anti-BRCA1 (Ab-1) Mouse mAb (MS110), liquid, clone MS110, Calbiochem®
SKU
Pack Size
Availability
Price
Quantity
Sigma-Aldrich
Monoclonal Anti-POLQ antibody produced in mouse, clone 1C11, purified immunoglobulin, buffered aqueous solution
SKU
Pack Size
Availability
Price
Quantity