Abstract 3282: Endocrine resistance genes driving cross-resistance to current combination therapies in HR-positive breast cancer
Authors: Zhangzan Huang, Noor Wortelboer, Corine Beaufort, Seda N. Ortak, Da-wei Chan, Hamit H. Dag, Jean Helmijr, John Martens, Maurice Jansen
Journal: Cancer Research (2024)

Abstract Introduction: Treatment failure to multiple treatment lines in hormone receptor positive (HR+) patients brings cross-resistance into the stage. The study aimed to determine if tamoxifen resistance genes cause cross-resistance to commonly employed metastatic breast cancer (combination) treatments. Materials &amp; Methods: Parental and tamoxifen resistant MCF7A models (BCAR3, BCAR4, EGFR, AKT1 and AKT2) were cultured for 10 days with different concentrations of tamoxifen and fulvestrant (endocrine therapy), ribo-, abema-, and palbociclib (CDK4/6 inhibitors) and alpelisib (PIK3CA inhibitor). Compounds were tested as mono- and combination therapy in replicate experiments estimating cell growth using the Sulforhodamine B assay and half maximal inhibitory concentration (IC50) was calculated by Graphpad PRISM v5 software. Resistance was declared when IC50 was significantly different from parental (p&amp;lt;0.05, Mann-Whitney U test). Results: The BCAR3, BCAR4 and EGFR models were not only resistant to tamoxifen but also to fulvestrant monotherapy (see table). In the two AKTs models the initial results could not be reproduced and were excluded from the study. The BCAR4 model was also resistant to all CDK4/6- and PIK3CA-inhibitors monotherapy. Analysis of the combination regimens demonstrated cross-resistance in the BCAR4 model for all compound combinations tested, in the EGFR model for all combinations except fulvestrant combined with alpelisib, and in the BCAR3 model only for tamoxifen combined with alpelisib. Discussion/Conclusion: Tamoxifen resistance genes BCAR3, BCAR4 and EGFR show various degrees of cross-resistance to other breast cancer treatments. It might be worthwhile to evaluate these genes or their associated biological pathways as predictive biomarkers for cross-resistance in HR+ breast cancer patients treated with the mentioned (combination) therapies. Summary of median IC50 (IQR) for different conditions parental BCAR3 BCAR4 EGFR AKT1 AKT2 Monotherapy Tamoxifen 9.8 (7.0) 47.3 (121) ** 2210 (1280) ** 515 (495) ** 8.0 (21.3) 3.8 (21.8) Fulvestrant 0.1 (0.35) 0.8 (0.8) ** 309 (407) ** 11.4 (37.7) ** Ribociclib 479 (285) 423 (1102) 3099 (1212)** 719 (669) Abemaciclib 94.9 (82.5) 28.9 (52.6) 206 (197) * 189 (172) Palbociclib 138 (163) 91.1 (107) 608 (347) ** 158 (128) Alpelisib 14.1 (676) 322 (94.0) 1424 (372) ** 375 (356) Combination therapy Tamoxifen with Ribociclib 1.7 (1.0) 17.2 (29.0) 111 (159) * 54.4 (35.8) * Abemaciclib 2.5 (1.9) 6.0 (10.7) 19.5 (15.0) ** 40.0 (53.6) * Palbociclib 1.6 (2.0) 5.4 (4.6) 74.9 (80.9) * 29.2 (3.1) * Alpelisib 2.1 (0.3) 9.6 (12.4)* 157 (69.9) * 17.8 (9.9) * Combination therapy Fulvestrant with Ribociclib 0.07 (0.02) 0.1 (0.3) 14.4 (8.8) * 6.9(16.8) * Abemaciclib 0.07 (0.02) 0.1 (0.1) 4.6 (2.6) ** 2.6 (6.5) * Palbociclib 0.2 (0.1) 0.2 (1.6) 5.6 (0.9) * 1.3 (1.5) * Alpelisib 0.05 (0.05) 1.6 (20.6) 13.3 (8.1) * 2.1 (0.9) *:p&amp;lt;0.05, **:p&amp;lt;0.01 compared to parental cell line. Citation Format: Zhangzan Huang, Noor Wortelboer, Corine Beaufort, Seda N. Ortak, Da-wei Chan, Hamit H. Dag, Jean Helmijr, John Martens, Maurice Jansen. Endocrine resistance genes driving cross-resistance to current combination therapies in HR-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3282.