Loss of Heterozygosity of BRCA1/2 as a Predictive Marker for Talazoparib Response

Avital Granit Mizrahi, Haneen Hamad, Ahinoam Gugenheim, Benjamin Nisman, Anna Kuznetz, Inna Ben David, Yael Gelfend, Sherri Cohen, Aviad Zick, Kim Sheva, Hovav Nechushtan, Tamar Peretz, Amichay Meirovitz

    Research output: Contribution to journalArticlepeer-review

    1 Scopus citations


    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.

    Original languageEnglish
    Pages (from-to)5257-5263
    Number of pages7
    JournalAnticancer Research
    Issue number11
    StatePublished - 1 Nov 2022


    • BRCA mutation
    • PARPi
    • heterozygosity
    • predictive marker
    • talazoparib

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research


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