Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway

• DOI: 10.1016/j.ccell.2018.11.006
• Publication Date: 2018-12-10T15:35:33Z
• Authors: Zhiqiang Li; Pedram Razavi; Qing Li; Weiyi Toy; Bo Liu; Christina Ping; Wilson Hsieh; Francisco Sanchez...; David N. Brown; Arnaud F. Da Cruz...; Luc Morris; Pier Selenica; Emily Eichenberger; Ronglai Shen; Nikolaus Schultz; Neal Rosen; Maurizio Scaltriti; Edi Brogi; Jose Baselga; Jorge S. Reis-Filho; Sarat Chandarlapaty
• Keywords: Mice, Knockout; 0303 health sciences; Cyclin-Dependent Kinase 4; Breast Neoplasms; Cyclin-Dependent Kinase 6; Mice, SCID; Protein Serine-Threonine Kinases; Cadherins; 3. Good health; 03 medical and health sciences; HEK293 Cells; Drug Resistance, Neoplasm; Loss of Function Mutation; Mice, Inbred NOD; Cell Line, Tumor; MCF-7 Cells; Animals; Humans; Female; Hippo Signaling Pathway; RNA Interference; Protein Kinase Inhibitors; Signal Transduction

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.