Interferon response gene signature linked to CDK4/6 inhibition resistance

By oncoXchange

December 12th 2019

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By Wayne Kuznar for oncoXchange

Aberrant interferon signaling is associated with intrinsic resistance to CDK4/6 inhibition in patients with estrogen receptor (ER)-positive breast cancer.

Molecular profiling of ER-positive breast cancer cell lines and breast cancer patients demonstrates that interferon signaling is associated with reduced sensitivity to CDK4/6 inhibition, and that an interferon-related palbociclib resistance signature (IRPS) predicts poor prognosis in luminal breast cancer patients, said Carmine De Angelis, MD, PhD, at the 2019 San Antonio Breast Cancer Symposium.

Despite the improvement in outcomes with CDK4/6 inhibition in combination with endocrine therapy in patients with metastatic ER-positive/HER2-negative breast cancer, intrinsic and acquired resistance to CDK4/6 inhibitors is common. “Deciphering the molecular basis for sensitivity and resistance to CDK4/6 inhibitors is crucial to identify predictive biomarkers as well as potential novel therapeutic targets to improve patient outcome,” said Dr. De Angelis, from Baylor College of Medicine, Houston.

Multiple breast cancer ER-sensitive and ER-resistant cell lines and tumor samples from two clinical trials of CDK4/6 inhibition in the neoadjuvant setting—NeoPalANA (palbociclib) and neoMONARCH (abemaciclib)—were analyzed.

Palbociclib was first assessed in a panel of cell lines, and was found to result in a dose-dependent inhibition of cell growth, though the degree of sensitivity varied among the models.

Gene cell enrichment analysis identified the interferon-alpha response and interferon-gamma response among the top ranked gene signatures enriched in cell lines resistant to palbociclib compared with those sensitive to palbociclib. Using gene expression data from the Cancer Dependency Map (DepMap), increased resistance to CDK4/6 knockdown by messenger RNA was associated with higher interferon signaling in ER-positive, HER2-negative cell lines.

In examining the correlation between the expression of genes belonging to the interferon gamma response and the interferon alpha response, using palbociclib IC50 values in cell lines, a total of 35 genes were found to be associated with a reduced response to palbociclib. This subset of genes was dubbed the “IRPS.”

To determine if the interferon signaling was associated with intrinsic resistance to CDK4/6 inhibitors in ER-positive/HER2-negative breast cancer patients, the researchers interrogated the baseline gene expression profile of CDK4/6 inhibitor-resistant tumor vs. sensitive tumor from the NeoPalANA and neoMONARCH trials. “This analysis revealed that the interferon gamma and the interferon alpha response as well as the IRPS were among the top enriched signatures in the CDK4/6-resistant tumors,” said Dr. De Angelis.

The behavior and prognostic value of the signature within primary breast cancer tumors was assessed in patients with ER-positive/HER2-negative breast cancer using the TCGA, METABRIC, and KMplot datasets. In this analysis, the IRPS score was found to be significantly higher in luminal B compared with luminal A subtypes in both the TCGA and METABRIC datasets. “We also found that patients with high IRPS breast cancer had a significantly lower breast cancer-specific survival compared with patients with low IRPS scores,” said Dr. De Angelis. “This result was independent of the luminal subtype.”

Higher expression of 14 of 35 IRPS genes was also found to be associated with worse relapse-free survival in endocrine-resistant breast cancer patients who were treated with adjuvant endocrine therapy.

In estimating the infiltration of immune and stromal cells within each tumor in the TCGA dataset, it was found that high IRPS tumors did not present with high infiltration of interferon-producing cells, suggesting that interferon signaling is tumor epithelial-derived in a substantial number of primary ER-positive, HER2-negative breast cancers. In addition, in ER-positive, HER-2 negative tumors, immune checkpoint expression was found to be significantly correlated with IRPS score. “Also, we found that the top two immune subsets that correlate with high IRPS score were the M1 macrophages and the immunosuppressive T regulatory cells,” said Dr. De Angelis.

Gene cell enrichment analysis also showed that interferon signaling was highly upregulated in cells with acquired resistance to palbociclib.

Future studies are warranted to provide mechanistic insights into the association between interferon signaling and response to CDK4/6 inhibition, said De Angelis, as well to investigate the therapeutic potential of combinations with immune checkpoint inhibitors.