Loss of FAT1 Drives Resistance to CDK4/6 Inhibitors in Breast Cancer

CDK4/6 inhibitors (CDK4/6i) are part of the standard-of-care treatment for patients with estrogen receptor–positive (ER⁺)/HER2⁻ breast cancer. Recently, potential mechanisms of resistance to CDK4/6 inhibitors have been identified in both patient samples and preclinical models, including RB loss and CDK6 amplification. To identify drivers of resistance to CDK4/6i, Li, Razavi, Li, and colleagues performed a genomic analysis of 348 post-CDK4/6i treated ER⁺ breast tumors. Patients harboring FAT1 loss-of-function mutations exhibited significantly decreased progression-free survival (PFS) compared with patients with missense FAT1 mutations or wild-type FAT1, and a similar PFS as patients with deleterious RB1 mutations. FAT1-deleted ER⁺, CDK4/6i-sensitive breast cancer cell lines exhibited the same level of proliferation as the parental cell lines and, unlike the parental cell lines, did not exhibit any decrease in proliferation after treatment with a CDK4/6i. Phosphorylation of the CDK4/6 substrate RB was partially decreased in FAT1-deleted cells, and the IC₅₀s of CDK4/6is were significantly increased in FAT1-deleted cells compared to parental cells. Further, CDK6 levels were increased in FAT1-deleted cells and ER⁺ tumors compared with wild-type FAT1 parental cells and ER⁺ tumors, respectively, and CDK6 levels were lower than CDK4 levels in parental cells and wild-type FAT1 ER⁺ tumors. Knockdown of CDK6 in FAT1-deleted cells restored CDK4/6i sensitivity whereas overexpression of CDK6 led to resistance. The Hippo pathway, which has previously been shown to be a target of FAT1, was found to be suppressed in FAT1-deleted cells; moreover, FAT1-deleted cells exhibited increases in the binding of YAP/TAZ to TEAD sites in the CDK6 promoter and the nuclear localization of YAP. Similarly, loss of NF2, a known regulator of Hippo signaling, resulted in increased CDK6 levels and CDK4/6i resistance in ER⁺ breast cancer cells. These results identify FAT1 loss–mediated CDK6 upregulation as a mechanism of CDK4/6i resistance and elucidate the role of Hippo signaling in ER⁺ breast cancer.

Li Z, Razavi P, Li Q, Toy W, Liu B, Ping C, et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway. Cancer Cell 2018;34:893–905.

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