title: Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer.
abstract: Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis, in part, via noncanonical cyclin D1-CDK2-mediated S-phase entry. This adaptation was prevented by cotreatment with hormone therapies or PI3K inhibitors, which reduced the levels of cyclin D1 (CCND1) and other G1-S cyclins, abolished pRb phosphorylation, and inhibited activation of S-phase transcriptional programs. Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient-derived tumor xenograft (PDX) models, resulting in tumor regression and improved disease control. Furthermore, a triple combination of endocrine therapy, CDK4/6, and PI3K inhibition was more effective than paired combinations, provoking rapid tumor regressions in a PDX model. Mechanistic investigations showed that acquired resistance to CDK4/6 inhibition resulted from bypass of cyclin D1-CDK4/6 dependency through selection of CCNE1 amplification or RB1 loss. Notably, although PI3K inhibitors could prevent resistance to CDK4/6 inhibitors, they failed to resensitize cells once resistance had been acquired. However, we found that cells acquiring resistance to CDK4/6 inhibitors due to CCNE1 amplification could be resensitized by targeting CDK2. Overall, our results illustrate convergent mechanisms of early adaptation and acquired resistance to CDK4/6 inhibitors that enable alternate means of S-phase entry, highlighting strategies to prevent the acquisition of therapeutic resistance to these agents. Cancer Res; 76(8); 2301-13. ©2016 AACR.
authors.affiliation: The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Herrera-Abreu
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Palafox
authors.affiliation: The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Uzma
authors.initials: U
authors.lastname: Asghar
authors.affiliation: Weill Cornell Medicine, Cornell University, New York, New York.
authors.forename: Martín A
authors.initials: MA
authors.lastname: Rivas
authors.affiliation: The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Rosalind J
authors.initials: RJ
authors.lastname: Cutts
authors.affiliation: The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Isaac
authors.initials: I
authors.lastname: Garcia-Murillas
authors.affiliation: The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Alex
authors.initials: A
authors.lastname: Pearson
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Guzman
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Rodriguez
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: Grueso
authors.affiliation: Medical Oncology, Hospital Vall d'Hebron, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Bellet
authors.affiliation: Medical Oncology, Hospital Vall d'Hebron, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Cortés
authors.affiliation: The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Elliott
authors.affiliation: The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Sunil
authors.initials: S
authors.lastname: Pancholi
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom. Academic Department of Biochemistry, Royal Marsden Hospital, London, United Kingdom.
authors.forename: Mitch
authors.initials: M
authors.lastname: Dowsett
authors.affiliation: The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom.
authors.forename: Lesley-Ann
authors.initials: LA
authors.lastname: Martin
authors.affiliation: The Breast Cancer Now Research Centre, Institute of Cancer Research, London, United Kingdom. Breast Unit, Royal Marsden Hospital, London, United Kingdom. nicholas.turner@icr.ac.uk vserra@vhio.net.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Turner
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain. nicholas.turner@icr.ac.uk vserra@vhio.net.
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug 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*; D019008:Drug Resistance, Neoplasm; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D010879:Piperazines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D011725:Pyridines; D011960:Receptors, Estrogen; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib