PTEN Loss Mediates Clinical Cross-Resistance to CDK4/6 and PI3Kα Inhibitors in Breast Cancer

Cancer Discov. 2020 Jan;10(1):72-85. doi: 10.1158/2159-8290.CD-18-0830. Epub 2019 Oct 8.


The combination of CDK4/6 inhibitors with antiestrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells, ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Because PTEN loss also causes resistance to PI3Kα inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment-sequencing strategies. SIGNIFICANCE: Our analysis of serial biopsies uncovered RB and PTEN loss as mechanisms of acquired resistance to CDK4/6 inhibitors, utilized as first-line treatment for ER-positive advanced breast cancer. Importantly, these findings have near-term clinical relevance because PTEN loss also limits the efficacy of PI3Kα inhibitors currently approved in the post-CDK4/6 setting.This article is highlighted in the In This Issue feature, p. 1.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aminopyridines / administration & dosage
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Apoptosis
  • Biomarkers, Tumor
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / pathology
  • Cell Proliferation
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Clinical Trials, Phase I as Topic
  • Cross-Sectional Studies
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Letrozole / administration & dosage
  • Mice
  • Mice, Nude
  • Middle Aged
  • PTEN Phosphohydrolase / deficiency*
  • PTEN Phosphohydrolase / genetics
  • Prognosis
  • Purines / administration & dosage
  • Receptors, Estrogen / metabolism
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays


  • Aminopyridines
  • Biomarkers, Tumor
  • Purines
  • Receptors, Estrogen
  • Letrozole
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • CDK4 protein, human
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • ribociclib