RT Journal Article
SR Electronic
T1 Loss of Heterozygosity of <em>BRCA1/2</em> as a Predictive Marker for Talazoparib Response
JF Anticancer Research
JO Anticancer Res
FD International Institute of Anticancer Research
SP 5257
OP 5263
DO 10.21873/anticanres.16032
VO 42
IS 11
A1 AVITAL GRANIT MIZRAHI
A1 HANEEN HAMAD
A1 AHINOAM GUGENHEIM
A1 BENJAMIN NISMAN
A1 ANNA KUZNETZ
A1 INNA BEN DAVID
A1 YAEL GELFEND
A1 SHERRI COHEN
A1 AVIAD ZICK
A1 KIM SHEVA
A1 HOVAV NECHUSHTAN
A1 TAMAR PERETZ
A1 AMICHAY MEIROVITZ
YR 2022
UL http://ar.iiarjournals.org/content/42/11/5257.abstract
AB Background/Aim: Tumor cell lines are essential tools in understanding the molecular mechanisms underlying cancer biology and therapeutic responses. Poly (ADP-ribose) polymerase inhibitors (PARPi) kill tumor cells harboring pathogenic mutations of BRCA DNA repair-associated genes 1/2 (BRCA1/2) and are approved to treat ovarian and metastatic breast cancer. Loss of heterozygosity (LOH) of the wild-type BRCA1/2 locus is suspected to increase cellular response to PARPi. To better elucidate the molecular mechanisms underlying PARPi sensitivity and resistance, this study assessed the responses of various pathogenic BRCA1/2-mutant cell lines to the PARPi talazoparib. Materials and Methods: Mutant cell lines were extracted and cultured from four surgically resected, human breast cancer specimens with different pathogenic BRCA1/2, one normal breast specimen and one ovarian cancer specimen. Mutation analysis was performed on all cell lines using genomic DNA extraction and polymerase chain reaction. Following treatment with talazoparib, cell growth was assessed using tetrazolium salt and half-maximal inhibitory concentration values were determined. Results: A partial correlation between different variants of pathogenic BRCA1/2 mutation and talazoparib susceptibility was found, with five of the cell lines exhibiting sensitivity to talazoparib. The most sensitive cell-line to talazoparib had LOH for BRCA1, while the breast cancer cell line harboring BRCA2 LOH was resistant to talazoparib. Conclusion: This study suggests that LOH does not necessarily correlate with PARPi efficacy. These results lay a foundation for future studies to utilize these novel cell lines to further elucidate the underlying molecular mechanisms of PARPi resistance and reveal new potential drug targets.