Journal
CANCER CELL
Volume 34, Issue 6, Pages 893-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.11.006
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Funding
- Cancer Couch Foundation
- Shen Family Fund
- Weinberg Family Fund
- Breast Cancer Research Foundation
- Breast Cancer Alliance Young Investigator Award
- NCI Cancer Center Support Grant (CCSG) [P30 CA08748]
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Cyclin dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) are effective in breast cancer; however, drug resistance is frequently encountered and poorly understood. We conducted a genomic analysis of 348 estrogen receptor-positive (ER+) breast cancers treated with CDK4/6i and identified loss-of-function mutations affecting FAT1 and RB1 linked to drug resistance. FAT1 loss led to marked elevations in CDK6, the suppression of which restored sensitivity to CDK4/6i. The induction of CDK6 was mediated by the Hippo pathway with accumulation of YAP and TAZ transcription factors on the CDK6 promoter. Genomic alterations in other Hippo pathway components were also found to promote CDK4/6i resistance. These findings uncover a tumor suppressor function of Hippo signaling in ER+ breast cancer and establish FAT1 loss as a mechanism of resistance to CDK4/6i.
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