The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer
| العنوان: | The Genomic Landscape of Intrinsic and Acquired Resistance to Cyclin-Dependent Kinase 4/6 Inhibitors in Patients with Hormone Receptor–Positive Metastatic Breast Cancer |
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| المؤلفون: | Patricia S Smith, Nikhil Wagle, Lacey M. Litchfield, Pingping Mao, Xueqian Gong, Levi A. Garraway, Valerie M. Jansen, Utthara Nayar, Gabriela N. Johnson, Ofir Cohen, Sara M. Tolaney, Jorge E. Buendia-Buendia, Adrienne G. Waks, Eric P. Winer, Ricardo Martinez, Nan Lin, Gerald Batist, Stephen Parsons, Maxwell R. Lloyd, Sean Buchanan, Xiang S. Ye, Karla Helvie, Quincy Chu, Gerard J. Oakley, Seth A. Wander, Chunping Yu, Melissa E. Hughes, John R. Stille, Dewey Kim, Jill D. Kremer, Kailey J. Kowalski, Flora Luo |
| المصدر: | Cancer Discovery. 10:1174-1193 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, MAPK/ERK pathway, Receptors, Steroid, Biopsy, Ubiquitin-Protein Ligases, Estrogen receptor, Antineoplastic Agents, Breast Neoplasms, Cell Cycle Proteins, medicine.disease_cause, Proto-Oncogene Proteins p21(ras), 03 medical and health sciences, 0302 clinical medicine, Breast cancer, Cell Line, Tumor, Exome Sequencing, Humans, Medicine, Protein Kinase Inhibitors, biology, business.industry, Kinase, Cyclin-dependent kinase 4, Genomics, medicine.disease, Metastatic breast cancer, Retinoblastoma Binding Proteins, 030104 developmental biology, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Checkpoint Kinase 1, Cancer cell, Cancer research, biology.protein, Female, KRAS, business, Proto-Oncogene Proteins c-akt |
| الوصف: | Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor–positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of estrogen receptor expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations—in AKT1, RAS, and AURKA—have not, to our knowledge, been previously demonstrated as mechanisms of resistance to CDK4/6i in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients.Significance:We identified eight distinct mechanisms of resistance to CDK4/6i present in 66% of resistant tumors profiled. Most of these have a therapeutic strategy to overcome or prevent resistance in these tumors. Taken together, these findings have critical implications related to the potential utility of precision-based approaches to overcome resistance in many patients with HR+ metastatic breast cancer.This article is highlighted in the In This Issue feature, p. 1079 |
| تدمد: | 2159-8290 2159-8274 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::bf4ba02ffa18791bc5e2dafc527cfa80Test https://doi.org/10.1158/2159-8290.cd-19-1390Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....bf4ba02ffa18791bc5e2dafc527cfa80 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 21598290 21598274 |
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