Abstract A006: Characterizing antitumor response of PARP inhibitor and synergy of docetaxel and PARP Inhibitor in BRCA1/2 mutant TNBC breast cancer PDX modelsJinxi Wang, Leilei Chen, Likun Zhang, Binchen Mao, Sheng Guo, Ludovic Bourre, Jingjing Wang, Rekha Pal
- Cancer Research
Introduction: BRCA1 and BRCA2 are tumor suppressor genes that produce proteins which help repair damaged DNA. Even though FDA-approved PARPi, like olaparib or talazoparib, are successful in some BRCA-associated breast cancers, the occurrence of PARPi’s resistance remains a therapeutic challenge. In this study, we investigated the antitumor response of olaparib and the synergy of docetaxel and olaparib in a cohort of TNBC PDX models which were originated from patients with different BRCA1/2 mutation status.
Methods: An efficacy study was conducted in 6 TNBC PDX models established subcutaneously in immunodeficient mice. Germline mutations of BRCA1/2 genes in the PDX models were determined by both RNA and whole exome sequencing. Animals were treated with docetaxel, olaparib, or olaparib plus docetaxel. The tumor growth inhibition (TGI) ratio of each treatment group was calculated at the end point, and the synergy score, defined as the difference between observed and expected TGI of the combination group in percentage, was determined.
Results: In vivo efficacy responses to olaparib varied across the panel of TNBC PDX models. BR9479 (BRAC2 mutant), originated from primary lesion of a chemotherapy-naïve patient, was sensitive to olaparib, with 87% TGI, while the BR9480 (BRAC2 mutant), which originated from the skin metastases lesion of the same patient after AC-T treatment, was completely resistant to olaparib treatment. A comparison of the genome sequences of this pair of models showed a MED12 gene (G1676D) variant, a deleterious mutation, which has been reported to confer resistance to olaparib in BRCA-deficient cells, associated with restoration of both homology repair (HR) and replication fork protection. BR9464, a BRCA1 mutated model with nonsynonymous variants (P871L, E1038G, K1183R) showed limited response to Olaparib with 19% TGI. While BR9457 with additional deleterious variants (D693N, Q356R) in BRCA1 showed 41% TGI to olaparib. Partial response to the PARPi was also observed in BR9465 (68% TGI) and BR9493 (39% TGI) carrying the PARP1 missense variant (V762A), which is associated with decreased PARylation activity. Chemotherapy induces DNA lesions and cytotoxicity in cancer cells, and when combined with inhibiting PARP1 DNA repair, the effectiveness of therapies can be increased. Similar to the olaparib single treatment, the combination of docetaxel and olaparib showed different synergies depending on the BRAC mutation status. Indeed, models BR9457 and BR9464 that carry BRCA1 (p.S1634G; p.K1183R; p.E1038G; p.P871L) variants and BRCA2 (p.V2466A) variants simultaneously present enhanced synergy with the combination treatment compared with other models.
Conclusion: The results presented in this study indicate complicated mechanisms related to the PARPi treatment response as well as potential synergy dependent on the different BRAC1/2 mutation status. The series of established BRCA-mutant breast cancer PDX models with different characters provides a valuable preclinical platform for the development of novel therapeutic strategies.
Citation Format: Jinxi Wang, Leilei Chen, Likun Zhang, Binchen Mao, Sheng Guo, Ludovic Bourre, Jingjing Wang, Rekha Pal. Characterizing antitumor response of PARP inhibitor and synergy of docetaxel and PARP Inhibitor in BRCA1/2 mutant TNBC breast cancer PDX models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A006.