LRRK2 inhibition potentiates PARP inhibitor cytotoxicity through inhibiting homologous recombination‐mediated DNA double strand break repair
Ovarian Neoplasms
0301 basic medicine
Medicine (General)
Mice, Nude
Recombinational DNA Repair
Antineoplastic Agents
Drug Synergism
Poly(ADP-ribose) Polymerase Inhibitors
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
LRRK2 inhibitor
3. Good health
Disease Models, Animal
Mice
03 medical and health sciences
PARP inhibitor
R5-920
Cell Line, Tumor
HR
Rad51
Animals
Humans
DNA Breaks, Double-Stranded
Female
Research Articles
DOI:
10.1002/ctm2.341
Publication Date:
2021-02-26T11:04:40Z
AUTHORS (13)
ABSTRACT
AbstractPARP inhibitors induce DNA lesions, the repair of which are highly dependent on homologous recombination (HR), and preferentially kill HR‐ deficient cancers. However, cancer cells have developed several mechanisms to transform HR and confer drug resistance to PARP inhibition. Therefore, there is a great clinical interest in exploring new therapies that induce HR deficiency (HRD), thereby sensitizing cancer cells to PARP inhibitors. Here, we found that GSK2578215A, a high‐selective and effective leucine‐rich repeat kinase 2 (LRRK2) inhibitor, or LRRK2 depletion suppresses HR preventing the recruitment of RAD51 to DNA damage sites through disruption of the interaction of RAD51 and BRCA2. Moreover, LRRK2 inhibition or depletion increases the susceptibility of ovarian cancer cells to Olaparib in vitro and in vivo. In clinical specimens, LRRK2 high expression is high related with advanced clinical characteristics and poor survival of ovarian cancer patients. All these findings indicate ovarian cancers expressing high levels of LRRK2 are more resistant to treatment potentially through promoting HR. Furthermore, combination treatment with an LRRK2 and PARP inhibitor may be a novel strategy to improve the effectiveness of LRRK2 expression ovarian cancers.
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CITATIONS (9)
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