AMG176, an MCL-1 inhibitor, is active in pre-clinical models of aggressive B-cell lymphomas

Abstract

Upregulation of the anti-apoptotic protein MCL-1 has been implicated in chemotherapy resistance and poor clinical outcomes in B-cell lymphoma (BCL). We report the activity of AMG176, a direct, selective MCL-1 inhibitor, in preclinical models of BCL. A panel of cell lines representing diffuse large B-cell lymphoma (DLBCL), double-hit lymphoma (DHL) and Burkitt’s lymphoma (BL) was selected. AMG176 induced apoptotic cell death in a dose- and time-dependent manner in all BCL cell lines. Baseline MCL-1 expression was not predictive of response. AMG176 exhibited impressive synergy with venetoclax and chemotherapeutic agents, less so with proteasomal inhibitors, and antagonism with anti-CD20 monoclonal antibodies. The activity of AMG176 could not be confirmed in murine models of BCL. Combination therapy targeting MCL-1 and BCL-2 may provide an alternative therapeutic approach in BCL, however optimal patient selection will remain the key to obtaining high response rates and tolerability.

Keywords:

• MCL-1 inhibitor
• venetoclax
• non-hodgkin lymphoma
• burkitt lymphoma
• diffuse large B-cell lymphoma
• double hit lymphoma

Author contributions

P.T., T.D., C.M., and J.G. performed research; P.T., T.D., C.M., J.G., M.B., F.J.H.I. designed the research study; P.T., T.D., C.M., J.G., M.B., and F.J.H.I. analyzed the data; P.T., C.M. J.G., P.G., M.B, and F.J.H.I., wrote and edited the paper. All authors give their approval for the final manuscript.

Disclosure statement

P.T. has served on the advisory boards for Kura Oncology, TG therapeutics, ADC therapeutics and Genentech and Lilly USA. T.R. has no conflicts of interest. C.M. has no conflicts of interest. J.G. has no conflicts of interest. P.G has received research support from Kite Pharma and served on advisory boards for Astra Zeneca, Daiichi Sankyo and Secura Bio. M.B has no conflicts of interest. F.J.H.I. have served on advisory boards for Millennium Pharmaceuticals, Pharmacyclics, Celgene, Amgen, Genentech, Kura Oncology and Seattle Genetics.

Additional information

Funding

This work was supported, in part, by grants from the National Cancer Institute [5RO1CA136907-02], the Eugene and Connie Corasanti Lymphoma Research Fund, the Czech Ministry of Health grant [IGA-MZ NT13201-4/2012] and institutional research grants [PRVOUK-27/LF1/1 and PRVOUK P24/LF1/3].