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

Abstract

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. Here, we screened genes associated with palbociclib resistance through genomics and transcriptomics in preclinical breast cancer models. Palbociclib-resistant cells were generated by exposing hormone receptor-positive breast cancer cell lines to palbociclib. Whole-exome sequencing (WES) and a mRNA microarray were performed to compare the genomic and transcriptomic landscape between both palbociclib-sensitive and resistant cells. Microarray analysis revealed 651 differentially expressed genes (DEGs), while WES revealed 107 clinically significant mutated genes. Furthermore, pathway analysis of both DEGs and mutated genes revealed immune pathway deregulation in palbociclib-resistant 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. In conclusion, our genomics and transcriptomics analysis using preclinical model, revealed that deregulated immune pathway is an additional mechanism of CDK4/6 inhibitor resistance besides the activation of cyclin E-CDK2 pathway and loss of RB, etc. Further studies are warranted to evaluate whether immune pathways may be a therapeutic target to overcome CDK4/6 inhibitor resistance.

Combination of Abemaciclib following Eribulin Overcomes Palbociclib-Resistant Breast Cancer by Inhibiting the G2/M Cell Cycle Phase

“…Furthermore, overlapping myelosuppression (e.g., neutropenia) is another concern when two myelosuppressing agents are combined. Some preclinical studies previously demonstrated the antagonism between CDK4/6 inhibitors and chemotherapeutic agents, where CDK4/6 inhibitors protected the cells from chemotherapeutic agents because both drugs were given simultaneously [ 35 , 36 ]. However, the sequential treatment of CDK4/6 inhibitor and chemotherapy synergistically potentiated the combination efficacy in other preclinical studies [ 34 , 37 ].…”

CDK4/6 inhibitor resistance: A bibliometric analysis

“…inhibitor and so on. The increased expression of CDK6 may be due to the deletion of the FAT1 gene (19, 34), and CDK2 overexpression may be due to the activation of the CCNE-CDK2 pathway (35,36). The causes of PI3K/AKT/mTOR pathway activation are a hot topic of research, including PTEN loss of function, AKT1 alteration, PI3K mutation, etc (37)(38)(39)(40)(41).…”

Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis

“…Cell-dependent kinase (CDK) is involved in many tumors related biological processes, such as cell cycle, immune checkpoint ( Hume et al, 2020 ), RNA transcription ( Al-Sanea et al, 2021 ), cell proliferation ( Liu J. et al, 2021 ). Recently, there have been studies on CDK4 ( Pandey et al, 2021 ) and CDK6 ( Pandey et al, 2021 ), but the mechanism of CDK2 ( El-Sattar et al, 2021 ) in cancer is relatively lacking. In our study, we deeply studied CDK2 and constructed the related immune prediction model.…”