title: Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence.
abstract: Dysregulated activation of the CDK4/6 kinases is a hallmark of most mammary-derived carcinomas. ATP-competitive inhibitors against this complex have been recently advanced in the clinic and have shown significant activity, particularly against tumors driven by the estrogen receptor (ER). However, resistance to these compounds has begun to emerge often months to years after their initiation. We investigated potential mechanisms of resistance using cell line models that are highly sensitive to this class of drugs. After prolonged exposure to the selective and potent CDK4/6 inhibitor LY2835219, clones emerged and several were found to harbor amplification of the CDK6 kinase. Amplification of CDK6 resulted in a marked increase in CDK6 expression and reduced response of the CDK4/6 target, phospho-Rb (pRb), to CDK4/6 inhibitors. Knockdown of CDK6 restored drug sensitivity, while enforced overexpression of CDK6 was sufficient to mediate drug resistance. Not only did CDK6 overexpression mediate resistance to CDK4/6 inhibitors but it also led to reduced expression of the ER and progesterone receptor (PR), and diminished responsiveness to ER antagonism. The reduced ER/PR expression after CDK4/6 inhibitor resistance was additionally observed in tumor biopsy specimens from patients treated with these drugs. Alternative mechanisms of resistance to CDK4/6 inhibitors such as loss of pRb and cyclin E1 overexpression also exhibited decreased hormone responsiveness, suggesting that the clinical paradigm of sequential endocrine-based therapy may be ineffective in some settings of acquired CDK4/6 resistance.
authors.affiliation: Oncology Department of the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.|Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Yang
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: T
authors.initials: T
authors.lastname: Bhatt
authors.affiliation: Breast Medicine Service, Department of Medicine, MSKCC, New York, NY, USA.|Weill Cornell Medical College, New York, NY USA.
authors.forename: M
authors.initials: M
authors.lastname: Dickler
authors.affiliation: Weill Cornell Medical College, New York, NY USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Giri
authors.affiliation: Weill Cornell Medical College, New York, NY USA.|Department of Pathology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.|Breast Medicine Service, Department of Medicine, MSKCC, New York, NY, USA.|Weill Cornell Medical College, New York, NY USA.
authors.forename: J
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Weill Cornell Medical College, New York, NY USA.|Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Rosen
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA.|Breast Medicine Service, Department of Medicine, MSKCC, New York, NY, USA.|Weill Cornell Medical College, New York, NY USA.
authors.forename: S
authors.identifier: 0000-0003-4532-8053
authors.initials: S
authors.lastname: Chandarlapaty
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000178:diet therapy / Q000201:enzymology* / Q000378:metabolism; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D005784:Gene Amplification; D006801:Humans; D061986:MCF-7 Cells; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D001562:Benzimidazoles; D047428:Protein Kinase Inhibitors; D011960:Receptors, Estrogen; C000590451:abemaciclib; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6