Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer
| العنوان: | Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer |
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| المؤلفون: | Britta Weigelt, Resel Pereira, C. Kent Osborne, Rinath Jeselsohn, Jiangang Liu, Vidyalakshmi Sethunath, Jamunarani Veeraraghavan, Rachel Schiff, Lanfang Qin, Luca Malorni, Pier Selenica, Carmine De Angelis, Xiaoyong Fu, Ilenia Migliaccio, David N Brown, Susan G. Hilsenbeck, Sarmistha Nanda, Joshua Donaldson, Valerie M. Jansen, Sara A. Hurvitz, Agostina Nardone, Dennis J. Slamon, Ben Ho Park, Tao Wang, Jorge S. Reis-Filho, Lacey M. Litchfield, C. Guarducci, Matteo Benelli, Maria Letizia Cataldo, Mothaffar F. Rimawi |
| المساهمون: | De Angelis, C., Fu, X., Cataldo, M. L., Nardone, A., Pereira, R., Veeraraghavan, J., Nanda, S., Qin, L., Sethunath, V., Wang, T., Hilsenbeck, S. G., Benelli, M., Migliaccio, I., Guarducci, C., Malorni, L., Litchfield, L. M., Liu, J., Donaldson, J., Selenica, P., Brown, D. N., Weigelt, B., Reis-Filho, J. S., Park, B. H., Hurvitz, S. A., Slamon, D. J., Rimawi, M. F., Jansen, V. M., Jeselsohn, R., Osborne, C. K., Schiff, R. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research, vol 27, iss 17 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Pyridines, Oncology and Carcinogenesis, Estrogen receptor, Antineoplastic Agents, Breast Neoplasms, Palbociclib, Piperazines, 03 medical and health sciences, 0302 clinical medicine, Immune system, Breast cancer, Receptors, Breast Cancer, Genetics, Tumor Cells, Cultured, Humans, Medicine, Oncology & Carcinogenesis, Cancer, Cultured, biology, business.industry, Kinase, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, medicine.disease, Estrogen, Immune checkpoint, Tumor Cells, Good Health and Well Being, 030104 developmental biology, Receptors, Estrogen, Oncology, 5.1 Pharmaceuticals, 030220 oncology & carcinogenesis, biology.protein, Cancer research, Female, Cyclin-dependent kinase 6, Development of treatments and therapeutic interventions, Signal transduction, business, Signal Transduction |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1557-3265 1078-0432 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5e8d5dea84c01cc54303c5f5ebf7c4dcTest https://doi.org/10.1158/1078-0432.ccr-19-4191Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....5e8d5dea84c01cc54303c5f5ebf7c4dc |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15573265 10780432 |
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