Neutralization of BCL-2/X L Enhances the Cytotoxicity of T-DM1 In Vivo

Mol Cancer Ther. 2019 Jun;18(6):1115-1126. doi: 10.1158/1535-7163.MCT-18-0743. Epub 2019 Apr 8.

Abstract

One of the most recent advances in the treatment of HER2+ breast cancer is the development of the antibody-drug conjugate, T-DM1. T-DM1 has proven clinical benefits for patients with advanced and/or metastatic breast cancer who have progressed on prior HER2-targeted therapies. However, T-DM1 resistance ultimately occurs and represents a major obstacle in the effective treatment of this disease. Because anti-apoptotic BCL-2 family proteins can affect the threshold for induction of apoptosis and thus limit the effectiveness of the chemotherapeutic payload, we examined whether inhibition of BCL-2/XL would enhance the efficacy of T-DM1 in five HER2-expressing patient-derived breast cancer xenograft models. Inhibition of BCL-2/XL via navitoclax/ABT-263 significantly enhanced the cytotoxicity of T-DM1 in two of three models derived from advanced and treatment-exposed metastatic breast tumors. No additive effects of combined treatment were observed in the third metastatic tumor model, which was highly sensitive to T-DM1, as well as a primary treatment-exposed tumor, which was refractory to T-DM1. A fifth model, derived from a treatment naïve primary breast tumor, was sensitive to T-DM1 but markedly benefited from combination treatment. Notably, both PDXs that were highly responsive to the combination therapy expressed low HER2 protein levels and lacked ERBB2 amplification, suggesting that BCL-2/XL inhibition can enhance sensitivity of tumors with low HER2 expression. Toxicities associated with combined treatments were significantly ameliorated with intermittent ABT-263 dosing. Taken together, these studies provide evidence that T-DM1 cytotoxicity could be significantly enhanced via BCL-2/XL blockade and support clinical investigation of this combination beyond ERBB2-amplified and/or HER2-overexpressed tumors.

Publication types

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

MeSH terms

  • Ado-Trastuzumab Emtansine / pharmacology
  • Ado-Trastuzumab Emtansine / therapeutic use*
  • Aniline Compounds / pharmacology*
  • Aniline Compounds / therapeutic use*
  • Animals
  • Antineoplastic Agents, Immunological / pharmacology
  • Antineoplastic Agents, Immunological / therapeutic use*
  • Apoptosis / drug effects
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Cytotoxicity, Immunologic / drug effects*
  • Drug Resistance, Neoplasm / drug effects
  • Drug Therapy, Combination
  • Female
  • Humans
  • Immunoconjugates / pharmacology
  • Immunoconjugates / therapeutic use*
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / metabolism
  • Sulfonamides / pharmacology*
  • Sulfonamides / therapeutic use*
  • Xenograft Model Antitumor Assays
  • bcl-X Protein / antagonists & inhibitors*

Substances

  • Aniline Compounds
  • Antineoplastic Agents, Immunological
  • BCL2 protein, human
  • BCL2L1 protein, human
  • Immunoconjugates
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • bcl-X Protein
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Ado-Trastuzumab Emtansine
  • navitoclax