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

Kamal Pandey,Hee Jung An,Seung Ki Kim,Seung Ah Lee,Eunbyeol Lee,Jin Hur,Nahee Park,Isaac Kim,Yong Wha Moon,Sohyun Hwang,Nar Bahadur Katuwal,Young Bin Cho

doi:10.3390/genes12020159

Kamal Pandey, Hee Jung An + Show 10 more

Open Access

https://doi.org/10.3390/genes12020159

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Journal: Genes	Publication Date: Jan 25, 2021
Citations: 16	License type: CC BY 4.0

Affiliation: CHA Bundang Medical Center, CHA University

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.

Highlights

Breast cancer, the most common type of cancer and one of the leading causes of mortality among women worldwide [1], can be classified into three subtypes, hormone receptor (HR)-positive, human epidermal growth factor receptor (HER) 2-positive, and triple negative breast cancer
A comparison between MCF7 and MCF7-PR cells identified 651 differentially expressed genes (DEGs), with Gene Ontology (GO) enrichment analysis revealing that 85 genes were involved in immune pathways (Figure 2A)
Type I IFN genes were found to have increased in MCF7-PR cells (Figure 2B), which was further validated by qRT-polymerase chain reaction (PCR) (Figure 2C)

Summary

Introduction

The most common type of cancer and one of the leading causes of mortality among women worldwide [1], can be classified into three subtypes, hormone receptor (HR)-positive, human epidermal growth factor receptor (HER) 2-positive, and triple negative breast cancer. HR-positive breast cancer has been the most common, constituting approximately 70% of all breast cancer subtypes [2]. Cyclin-dependent kinase (CDK) 4/6 inhibitors in combination with endocrine therapy had been approved by the US Food and Drug Administration as a first-or second-line treatment of HR-positive/ HER2-negative breast cancer [3]. Several mechanisms associated with CDK4/6 inhibitor resistance, including RB loss [8], cyclin E overexpression [9], FGFR amplification [10], PTEN loss [11], and MDM2 amplification [12], have been investigated, no clinical biomarker and validated strategies for overcoming CDK4/6 inhibitor resistance are as yet available

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