American Association for Cancer Research
15357163mct180743-sup-204654_2_supp_5312528_pm59yy.pdf (708.23 kB)

Supplementary Figure 6 from Neutralization of BCL-2/XL Enhances the Cytotoxicity of T-DM1 In Vivo

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journal contribution
posted on 2023-04-03, 15:21 authored by Jason J. Zoeller, Aleksandr Vagodny, Krishan Taneja, Benjamin Y. Tan, Neil O'Brien, Dennis J. Slamon, Deepak Sampath, Joel D. Leverson, Roderick T. Bronson, Deborah A. Dillon, Joan S. Brugge

HER2 levels post-treatment.



Dana-Farber Harvard Cancer Center Breast SPORE

American Association for Cancer Research

Breast Cancer Research Foundation

Department of Defense Breast Cancer Research Breakthrough Award



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.

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