Abstract 5722: Gene expression analysis of different PARPi combination approaches with carboplatin at primary tumor and metastatic site in xenograft model of triple-negative breast cancer
Authors: Djihane Abdesselam, Mallory Frederick, Saima N. Hassan
Journal: Cancer Research (2025)

Introduction: Patients with triple-negative breast cancer (TNBC) do not overexpress hormone receptors or HER2, leaving limited therapeutic options. Despite the improvement in outcomes for patients with early TNBC, patients only benefit from one targeted therapeutic agent: PARP inhibitors (PARPi). By targeting PARP-1/2, PARPi function via catalytic inhibition, thereby inducing synthetic lethality in BRCA1/2-mutant contexts, or via PARP-DNA trapping. Two potent PARPi have demonstrated efficacy in the clinic amongst BRCA1/2-mutant patients, with talazoparib and olaparib improving progression-free survival in the metastatic setting, and olaparib improving overall survival in the adjuvant setting. However, PARPi have also demonstrated efficacy amongst BRCA-wild type tumors in the pre-clinical setting. We have demonstrated that the concomitant combination of talazoparib and carboplatin (Conc T+C) was synergistic in 92% of TNBC cell lines. However, the sequential combination of talazoparib-first, followed by carboplatin (Seq T-&amp;gt;C) demonstrated marked inhibition of migration, invasion, and distant lung metastasis. Therefore, we wanted to better understand the underlying mechanism of efficacy of the Seq T-&amp;gt;C combination approach. Methods: We performed RNAseq gene expression analysis of the metastatic lung and primary tumors from MDAMB231 orthotopic xenograft mouse model, to compare the different combination approaches including Conc T+C, Seq T-&amp;gt;C, and carboplatin-first followed by talazoparib (Seq C-&amp;gt;T). Results: Principal component analysis showed that Seq C-&amp;gt;T was grouped closely with Conc T+C in the primary tumor and metastatic lung tissue. At the metastatic site, Seq T-&amp;gt;C was associated with a downregulation of the homologous recombination, DNA replication, and mismatch repair pathways in the metastatic lung tissue. In the primary tumor, Seq C-&amp;gt;T was associated with a downregulation of the homologous recombination pathway. However, Seq C-&amp;gt;T and Conc T+C shared several similar upregulated pathways in the primary tumor, including epithelial-mesenchymal transition, angiogenesis, and an inflammatory response. Conclusion: The Seq T-&amp;gt;C approach demonstrated an exclusive downregulation of DNA damage response pathways at the metastatic site, suggesting a differential effect at the primary tumor and distant metastatic site. The Seq C-&amp;gt;T and Conc T+C combination approaches were both associated with an upregulation of several pathways associated with treatment resistance. Therefore, PARPi-first combination with carboplatin may be an effective therapeutic approach to inhibit the development of distant metastasis. Citation Format: Djihane Abdesselam, Mallory Frederick, Saima N. Hassan. Gene expression analysis of different PARPi combination approaches with carboplatin at primary tumor and metastatic site in xenograft model of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5722.