Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer

Maria Teresa Herrera-Abreu, Marta Palafox, Uzma Asghar, Martín A Rivas, Rosalind J Cutts, Isaac Garcia-Murillas, Alex Pearson, Marta Guzman, Olga Rodriguez, Judit Grueso, Meritxell Bellet, Javier Cortés, Richard Elliott, Sunil Pancholi, José Baselga, Mitch Dowsett, Lesley-Ann Martin, Nicholas C Turner, Violeta Serra

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2301-13
Number of pages13
JournalCancer Research
Volume76
Issue number8
DOIs
Publication statusPublished - 15 Apr 2016

Keywords

  • Animals
  • Antineoplastic Agents/pharmacology
  • Breast Neoplasms/drug therapy
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4/antagonists & inhibitors
  • Cyclin-Dependent Kinase 6/antagonists & inhibitors
  • Drug Resistance, Neoplasm
  • Female
  • Heterografts
  • Humans
  • Mice
  • Piperazines/therapeutic use
  • Pyridines/therapeutic use
  • Receptors, Estrogen/metabolism

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