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Resistance Mechanisms to CDK4/6 Blockade in Advanced HR-Positive, HER2-Negative Breast Cancer and Emerging Therapeutic Opportunities

2021 Year in Review - Breast Cancer - Breast Cancer

The most common breast cancer subtype is hormone receptor (HR)-positive, HER2-negative breast cancer, and endocrine therapy is still the most effective treatment. The addition of cyclin-dependent kinase (CDK)4/6 inhibitors (ie, palbociclib, ribociclib, abemaciclib) to endocrine therapy has significantly improved the outcomes of patients with HR-positive advanced breast cancer.1

Several preclinical and translational studies have begun to offer light on the genetic and molecular landscape underlying resistance to these drugs. Changes affecting cell-cycle mediators and activation of oncogenic signal transduction pathways are 2 major drivers of CDK4/6 inhibitor treatment resistance. Next-generation sequencing of resistant tumor biopsies in the clinic identified the resistance drivers with the greatest translational evidence supporting their hypothesized role, which were then verified in laboratory models of HR-positive breast cancer. The mitotic spindle regulator Aurora Kinase A (AURKA), as well as the AKT/MAPK signaling pathways, have all been identified as common, therapeutically actionable resistance nodes. Precision-guided therapy techniques are currently being tested in clinical trials based on these findings.2

The main target of CDK4/6 is the tumor suppressor retinoblastoma. In preclinical studies, loss of retinoblastoma was found to be a driver of CDK4/6 inhibitor resistance.1

CDK4/6 inhibitors revolutionized the treatment of HR-positive, HER2-negative metastatic breast cancer, improving critical clinical outcomes while maintaining a manageable safety profile. The mechanism of action of CDK4/6 inhibitors and their implications in contemporary clinical practice are being studied to fully understand all the mechanisms of resistance.1


  1. Roberto M, Astone A, Botticelli A, et al. CDK4/6 inhibitor treatments in patients with hormone receptor positive, HER2 negative advanced breast cancer: potential molecular mechanisms, clinical implications and future perspectives. Cancers (Basel). 2021;13:332.
  2. Lloyd MR, Spring LM, Bardia A, Wander SA. Mechanisms of resistance to CDK4/6 blockade in advanced hormone receptor-positive, HER2-negative breast cancer and emerging therapeutic opportunities. Clin Cancer Res. 2021 Nov 1. Epub ahead of print.
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