Abstract P1-21-06: Deregulated immune pathway associated with palbociclib resistance in breast cancer preclinical models: Integrative analysis of genomics and transcriptomics

Abstract

Abstract Background: Recently CDK4/6 inhibitors are being widely used to treat advanced HR-positive breast cancer. Despite promising clinical outcomes, almost all patients eventually acquire resistance to CDK4/6 inhibitors. Hence, understanding the mechanisms of acquired resistance to CDK4/6 inhibitors is crucial to develop alternate treatment strategy. Therefore, we screened genes associated with palbociclib resistance through genomics and transcriptomics in breast cancer preclinical models. Methods: We generated palbociclib-resistant cell lines, MCF7-PR and T47D-PR by exposing MCF7 and T47D cells to palbociclib for over 9 months. After confirming the acquired resistance through in vitro assays, we performed whole exome sequencing (WES) and mRNA microarray to compare genomic and transcriptomic landscape between palbociclib-sensitive and resistant cells. Real-time PCR was performed to confirm differentially expressed genes. Results: Microrray analysis revealed 651 differentially expressed genes (DEGs) (fold change ≥2) by comparing MCF7 vs. MCF7-PR cells. WES also revealed 107 mutated genes by comparing T47D vs. T47D-PR cells. Further, GO annotation of both the DEGs and mutated genes found deregulation of immune pathway commonly in MCF7-PR and T47D-PR (FDR<0.25). Representatively, activated type I interferon pathway was notable in MCF7-PR cells with annotation of the DEGs. By real-time PCR, IRF9 and SP100 were commonly increased in the resistant cells (MCF7-PR, T47D-PR) compared to each sensitive counterpart. Besides, STAT1, IFI27, IFIT2, IFIT3, and XAF1 were increased in the MCF7-PR compared to MCF7, STAT2 was also increased in the T47D-PR compared to T47D. Regarding mutations found in resistant cells, MUC4 (in MCF7-PR) and MUC16 (in T47D-PR) mutations were annotated as immune pathway including immune response activating cell surface receptor signaling or O-glycan processing, et al. Besides, RB1 mutation was detected in T47D-PR cells. Conclusions: Deregulated immune pathway was found to be associated with palbociclib resistance in preclinical breast cancer models. Further studies are warranted to evaluate whether immune pathway may be a therapeutic target to overcome CDK4/6 inhibitor resistance. Citation Format: Yong Wha Moon, Eunbyeol Lee, Sohyun Hwang, Kamal Pandey, Nahee Park, Jin Hur, Young Bin Cho, Seung Ki Kim, Seung Ah Lee, Hee-Jung An, Joohyuk Sohn. Deregulated immune pathway associated with palbociclib resistance in breast cancer preclinical models: Integrative analysis of genomics and transcriptomics [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-21-06.