Background: Several CDK 4/6 inhibitors have recently been approved in combination with letrozole or fulvestrant in hormone receptor-positive breast cancer. Although this combination therapy has been found effective in some patients, resistance often develops. To aid in developing new therapies for CDK4/6 inhibitor-resistant breast cancer and better understand potential resistance mechanisms, we established a panel of nine XPDX models from eight female patients with luminal A breast cancer at time of progression following acquired resistance to CDK4/6 inhibitor therapy. These models, designated ST940C, ST2056, ST3164B, ST3164B/PBR, ST3932, ST4316B, ST4378, STF160, and STM001B were developed in athymic nude mice and characterized for receptor expression, genomic alterations, and in vivo drug sensitivity. Methods: STF160 was established from a primary biopsy and ST3932 from a metastatic soft tissue lesion; the remaining models were established from malignant fluid samples collected at various stages of treatment post CDK4/6 inhibitor response and progression. The resulting models were passaged and challenged with CDK4/6 inhibitors to confirm resistance and fulvestrant to assess sensitivity. Receptor expression was determined immunohistochemically. Genomic analysis, including WES and RNAseq, were performed to characterize models and identify mechanisms of resistance. For in vivo studies, palbociclib and abemaciclib were dosed by oral administration once daily at 50 mg/kg and fulvestrant by subcutaneous administration once weekly at 2.5 mg. In vivo study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20 versus control was considered sensitive. Tumor regression (%T/C<0) versus Day 0 tumor volume was also reported. Results: All models retained ER expression in evaluated passages with similar histology compared with archival clinical samples; HER2 positivity was also confirmed in ST940C which was established from a clinically ER+/HER2+ patient. DNA/RNA sequencing identified several model-specific variants including the ESR1Y537S mutation in ST940C and ST2056 and the ESR1-CCDC170 fusion in ST3164B and ST3164B/PBR; BRCA2Q1089Sfs*10 was identified in ST4316B and PIK3CAE545G in ST4378. In vivo, seven models including ST3164B, ST3164B/PBR, ST3932, ST4316B, ST4378, STF160, and STM001B were found resistant (%T/C>20) to palbociclib or abemaciclib and single agent fulvestrant. ST940C and ST2056 were sensitive (%T/C≤20) to tested CDK4/6 inhibitors but resistant to fulvestrant. Conclusion: We have established and characterized a panel of nine XPDX models from eight female patients with luminal A breast cancer at time of progression following acquired resistance to CDK4/6 inhibitor therapy, seven of which were found resistant to single agent palbociclib and abemaciclib and all nine to fulvestrant. This panel can be utilized as a valuable tool in better understanding CDK4/6 inhibitor resistance and in developing novel therapies for CDK4/6 inhibitor-resistant patients.

Citation Format: Tatiana Hernandez, Dustin Kneifel, Alyssa Simonson, Johnnie R Flores, Sarah Quick, April Cabang, Alexandra Ulmer, Kyriakos Papadopoulos, Amy Lang, Gladys Rodriguez, Murali Beeram, Drew Rasco, Amita Patnaik, Scott Ulmer, Michael J Wick. Establishment and characterization of luminal A breast XPDX models from patients with acquired resistance to CDK 4/6 inhibitors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-06.