HDAC Inhibitor Panobinostat Engages Host Innate Immune Defenses to Promote the Tumoricidal Effects of Trastuzumab in HER2+ Tumors.

Mikolaj Medon,Misty R Jenkins,Ricky W Johnstone,Eva Vidacs,Mark J Smyth,Kelly M Ramsbottom,Jason Li,Peter W Atadja,Joseph A Trapani,Phillip K Darcy,Michael A Henderson,Nicole M Haynes,Stephin J Vervoort

doi:10.1158/0008-5472.can-16-2247

Abstract

Histone deacetylase inhibitors (HDACi) may engage host immunity as one basis for their antitumor effects. Herein, we demonstrate an application of this concept using the HDACi panobinostat to augment the antitumor efficacy of trastuzumab (anti-HER2) therapy, through both tumor cell autonomous and nonautonomous mechanisms. In HER2+ tumors that are inherently sensitive to the cytostatic effects of trastuzumab, cotreatment with panobinostat abrogated AKT signaling and triggered tumor regression in mice that lacked innate and/or adaptive immune effector cells. However, the cooperative ability of panobinostat and trastuzumab to harness host anticancer immune defenses was essential for their curative activity in trastuzumab-refractory HER2+ tumors. In trastuzumab-resistant HER2+ AU565pv xenografts and BT474 tumors expressing constitutively active AKT, panobinostat enhanced the antibody-dependent cell-mediated cytotoxicity function of trastuzumab. IFNγ-mediated, CXCR3-dependent increases in tumor-associated NK cells underpinned the combined curative activity of panobinostat and trastuzumab in these tumors. These data highlight the immune-enhancing effects of panobinostat and provide compelling evidence that this HDACi can license trastuzumab to evoke NK-cell-mediated responses capable of eradicating trastuzumab-refractory HER2+ tumors. Cancer Res; 77(10); 2594-606. ©2017 AACR.

Highlights

20% to 30% of breast cancers overexpress the HER2/neu oncogene–encoding HER2 [1]
Trastuzumab suppressed the proliferation of BT474 tumor cells in a dose-dependent manner (Fig. 1A) and increased their sensitivity to panobinostat-induced cell death as determined by Annexin-V/propidium iodine (PI) staining (Fig. 1B)
Similar responses to panobinostat and trastuzumab treatment, alone and in combination were observed in SCID mice orthotopically transplanted with BT474 tumors (Fig. 1D)

Summary

Introduction

20% to 30% of breast cancers overexpress the HER2/neu oncogene–encoding HER2 [1]. Active dimers of HER2 with other family members promote tumorigenesis by enhancing tumor cell growth and survival [2]. Targeted blockade of HER2 signaling with the humanized antibody (Ab) trastuzu-. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). N.M. Haynes and R.W. Johnstone contributed and are co-senior authors of this article

Methods

Results

Conclusion