Deregulated Immune Pathway Associated with Palbociclib Resistance in Preclinical Breast Cancer Models: Integrative Genomics and Transcriptomics

Abstract Background: Recently, cyclin-dependent kinase (CDK) 4/6 inhibitors have been widely used to treat advanced hormone receptor-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 for developing alternative treatment strategies. Therefore, the present study screened genes associated with palbociclib resistance through genomics and transcriptomics in preclinical breast cancer models. Methods: Palbociclib-resistant cells, MCF7-PR and T47D-PR, were generated by exposing MCF7 and T47D cells to palbociclib. After confirming acquired resistance through in vitro assays, whole-exome sequencing (WES) and mRNA microarray were performed to compare the genomic and transcriptomic landscape between palbociclib-sensitive and resistant cells. Real time-PCR was performed to confirm differentially expressed genes.Results: Microarray analysis comparing MCF7 and MCF7-PR cells revealed 651 differentially expressed genes (DEGs) (fold change >2 or <0.5), while WES comparing T47D and T47D-PR cells revealed 107 mutated genes. Furthermore, pathway analysis of both DEGs and mutated genes revealed immune pathway deregulation commonly observed in MCF7-PR and T47D-PR cells. Notably, DEG annotation revealed activation of type I interferon pathway, activation of immune checkpoint inhibitory pathway, and suppression of immune checkpoint stimulatory pathway in palbociclib-resistant cells. Moreover, mutations in NCOR1, MUC4 and MUC16 genes found in palbociclib-resistant cells were annotated to be related to the immune pathway. Conclusions: Palbociclib resistance was found to be associated with deregulated immune pathway in preclinical breast cancer models. Further studies are warranted to evaluate whether immune pathways may be a therapeutic target to overcome CDK4/6 inhibitor resistance.