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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.
Pubmed ID: 30537512 RIS Download
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View all literature mentionsPrecision oncology knowledge base which contains information about the effects and treatment implications of specific cancer gene alterations. OncoKB contains detailed information about specific alterations in 418 cancer genes. Each variant entry contains biological effect, prevalence, prognostic information, and treatment implications. Information is curated from various sources, such as guidelines from the FDA, ClinicalTrials.gov, and scientific literature by a network of clinical fellows, research fellows, and faculty members at Memorial Sloan Kettering Cancer Center.
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