The Synergistic Antitumor Activity of Entinostat (MS-275) in Combination with Palbociclib (PD 0332991) in ER-Positive and TN Breast Cancer

Conference Correspondent  - SABCS

 

Given their potent clinical efficacy, CDK4/6 inhibitors used in combination with hormone receptor (HR) blockade (with an aromatase inhibitor or fulvestrant) are emerging as the standard of care for patients with metastatic HR-positive, HER2-negative breast cancers. The CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib are FDA approved for use in patients with HR-positive breast cancer. It has been observed that approximately 74% (25/34) of breast cancer cell lines have high phosphorylated Rb (phospho-Rb) expression levels and that triple-negative (TN) breast cancer cell lines often expressed phospho-Rb, suggesting that targeting phospho-Rb via CDK4/6 inhibition may be effective against TN breast cancer.1 The histone deacetylase (HDAC) inhibitors increase p21Cip1 levels, promoting proteasomal degradation of cyclin B1 and resulting in G2/M arrest. Entinostat is an oral, class 1, selective HDAC inhibitor currently in phase 3 testing in HR-positive breast cancer. Preclinical and clinical data demonstrate that entinostat, in combination with HR blockade, has anticancer activity.2 Based on these findings, the authors hypothesized that entinostat-induced apoptosis and palbociclib-induced cell cycle arrest can synergize to produce enhanced antitumor effects in estrogen receptor (ER)-positive breast cancer and TN breast cancer cell lines with high phospho-Rb expression levels.

To test this hypothesis, the authors assessed the combination’s antitumor effects and their mechanisms via CellTiter Blue and sulforhodamine B assays, flow cytometry, apoptosis (caspase 3/7) assays, anchorage-independent growth assays, Western blotting, reverse phase protein array (RPPA), and mammary fat pad xenograft mouse models.3 RPPA data showed that ER-positive and TN breast cancer cell lines more often expressed phospho-Rb than did other breast cancer cell subtypes (7/10 and 8/17 cell lines, respectively). The combination of entinostat and palbociclib synergistically inhibited tumor cell proliferation (combinational index <1.0), reduced in vitro colony formation (P <.05), inhibited in vivo tumor growth in ER-positive MCF-7 breast cancer cells (P <.05), and inhibited tumor growth in TN breast cancer xenograft mouse models (MDA-MB-231) more effectively than did either drug alone.

The authors concluded that, taken together, the data provide evidence that combining entinostat with palbociclib enhances the antitumor effects of these drugs. These findings justify conducting a clinical trial of combination treatment with entinostat and palbociclib in patients with ER-positive breast cancer or TN breast cancer.

References

  1. Chen SH, et al. Oncogene. 2017 Oct 23. doi: 10.1038/onc.2017.384. Epub ahead of print.
  2. Trapani D, et al. Expert Opin Investig Drugs. 2017;26:965-971.
  3. Lee J, et al. SABCS 2017. Abstract P5-21-15.
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Last modified: April 27, 2020