Journal
CANCER DISCOVERY
Volume 10, Issue 8, Pages 1174-1193Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-19-1390
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Funding
- Department of Defense [W81XWH-13-1-0032]
- Landon Foundation-AACR INNOVATOR Award [13-60-27-WAGL]
- NCI Breast Cancer SPORE at DF/HCC [P50CA168504]
- Susan G. Komen [CCR15333343]
- V Foundation
- Breast Cancer Alliance
- Cancer Couch Foundation
- Breast Cancer Research Foundation
- ACT NOW
- Fashion Footwear Association of New York
- Friends of Dana-Farber Cancer Institute
- National Comprehensive Cancer Network/Pfizer Independent Grant for Learning Change
- Dana-Farber Cancer Institute T32
- Wong Family Translational Research Award
- Conquer Cancer Foundation/Twisted Pink/American Society of Clinical Oncology Young Investigator Award
- Twisted Pink
- Hope Scarves
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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.
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