Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer

Abstract

Purpose: Cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (CDK4/6i) are highly effective against estrogen receptor–positive (ER+)/HER2− breast cancer; however, intrinsic and acquired resistance is common. Elucidating the molecular features of sensitivity and resistance to CDK4/6i may lead to identification of predictive biomarkers and novel therapeutic targets, paving the way toward improving patient outcomes. Experimental Design: Parental breast cancer cells and their endocrine-resistant derivatives (EndoR) were used. Derivatives with acquired resistance to palbociclib (PalboR) were generated from parental and estrogen deprivation–resistant MCF7 and T47D cells. Transcriptomic and proteomic analyses were performed in palbociclib-sensitive and PalboR lines. Gene expression data from CDK4/6i neoadjuvant trials and publicly available datasets were interrogated for correlations of gene signatures and patient outcomes. Results: Parental and EndoR breast cancer lines showed varying degrees of sensitivity to palbociclib. Transcriptomic analysis of these cell lines identified an association between high IFN signaling and reduced CDK4/6i sensitivity; thus an “IFN-related palbociclib-resistance Signature” (IRPS) was derived. In two neoadjuvant trials of CDK4/6i plus endocrine therapy, IRPS and other IFN-related signatures were highly enriched in patients with tumors exhibiting intrinsic resistance to CDK4/6i. PalboR derivatives displayed dramatic activation of IFN/STAT1 signaling compared with their short-term treated or untreated counterparts. In primary ER+/HER2− tumors, the IRPS score was significantly higher in lumB than lumA subtype and correlated with increased gene expression of immune checkpoints, endocrine resistance, and poor prognosis. Conclusions: Aberrant IFN signaling is associated with intrinsic resistance to CDK4/6i. Experimentally, acquired resistance to palbociclib is associated with activation of the IFN pathway, warranting additional studies to clarify its involvement in resistance to CDK4/6i.

Transcription Regulation and Genome Rewiring Governing Sensitivity and Resistance to FOXM1 Inhibition in Breast Cancer

“…These rewired genes ( Figure 2 and Table 1 ) included genes associated with interferon alpha and gamma response, epithelial mesenchymal transition (EMT), the p53 pathway, and TNFα signaling via NFκB. Of note, the upregulation of interferon alpha and gamma signaling we observed in ER-positive NB73-resistant cells is also reported to be observed in endocrine-resistant ER-positive breast cancers [ 12 ].…”

Unraveling Immune-Related lncRNAs in Breast Cancer Molecular Subtypes

“…Interestingly, most LumA and LumB lncRNAs were related positively or negatively to the Interferon Gamma Response module. Recently, a study demonstrated that the activation of the interferon signaling pathway in ER+ BRCA relates to resistance to CDK4/6 inhibitors and immune checkpoint activation (40). Understanding the role of lncRNAs in this context may be the subject of future studies.…”

MDM2 as a Rational Target for Intervention in CDK4/6 Inhibitor Resistant, Hormone Receptor Positive Breast Cancer

“…Mutation of the FAT Atypical Cadherin 1 (FAT1) gene has also been identified at a small percentage of clinical samples (17), leading to dysregulation of the HIPPO pathway through the accumulation of key HIPPO pathway components and increased expression of CDK6. Other proposed mechanisms of CDK4/6i resistance include 1) upregulation of cyclin D isoforms (18)(19)(20), which may underlie the relative ineffectiveness of palbociclib and ribociclib as a single agent in the absence of an endocrine therapy backbone as ERa is still free to promote expression of cyclin D; 2) dysregulated early phosphorylation of pRb by CDK2 (21,22); 3) upregulation of proliferative signalling leading to pRb hyperphosphorylation via dysregulation of the phosphatidylinositol 3 kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways, for example via upregulation of FGFR signalling (19,20,23,24); and 4) deregulation of immune associated pathways, for example increased interferon a and interferon g signalling that has been linked to reduced sensitivity and resistance and to CDK4/6i in clinical samples and preclinical models (25)(26)(27).…”