Abstract
Poly-ADP Ribose Polymerase (PARP) inhibitors are clinically approved for the treatment of homologous recombination (HR) repair deficient tumors. PARP targeted therapy has limited efficacy in HR-proficient cancer. In this study, we identified the non-receptor lymphocyte-specific protein tyrosine kinase (LCK) as a novel regulator of HR repair pathways in endometrioid epithelial ovarian cancer (eEOC). Inhibition of LCK attenuates the expression of RAD51, BRCA1, and BRCA2 proteins necessary for HR-mediated DNA repair. HR repair in eEOC cells is LCK dependent. Upon DNA damage LCK expression is increased, and autophosphorylated, activated LCK is localized in the nucleus. LCK inhibition impairs RAD51 foci formation but augments γH2AX formation during DDR indicating reduced ability to repair DNA damage. DNA damage leads to direct interaction of LCK with RAD51 and BRCA1. Finally, attenuation of LCK sensitized HR-proficient eEOC cells to PARP inhibitor. Collectively, the findings identify a mechanism for expanding utility of PARP inhibitors.
In Brief Dey and colleagues identify the nonreceptor tyrosine kinase LCK as a mediator of homologous recombination directed DNA repair in ovarian cancer. The studies show that LCK inhibition (LCKi) is sufficient to augment Poly (ADP-Ribose) Polymerase inhibitor efficacy in Homologous Recombination (HR) proficient endometrioid ovarian cancer.
Highlights
Nonreceptor tyrosine kinase LCK regulates expression of HR repair proteins RAD51, BRCA1 and BRCA2.
LCKi induces HR deficiency in endometrioid epithelial ovarian cancer.
DNA damage leads to autophosphorylation of LCK and co-immunoprecipitation with RAD51 and BRCA1.
LCKi potentiates PARP targeted therapy in HR proficient ovarian cancer and expands the utility of the highly successful PARP inhibitors in the clinic.
Statement of significance This study identifies a novel regulator and signaling pathway for maintaining HR repair during DNA damage. It further demonstrates a new opportunity to increase the utility of PARP inhibitors in HR-proficient eEOC cells.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵+ co-first authors
Conflict of interest: Authors declare no conflict of interest.
Abbreviations: eEOC: Endometrioid epithelial ovarian cancer, HR: Homologous recombination, LCK: Lymphocyte-specific protein tyrosine kinase, PARP: Poly ADP Ribose polymerase, DDR: DNA damage response, NHEJ: Non homologues end joining.