Targeting MCL-1 in hematologic malignancies: Rationale and progress

Andrew H Wei; Andrew W Roberts; Andrew Spencer; Aaron Seth Rosenberg; David Siegel; Roland B Walter; Sean Caenepeel; Paul Hughes; Zach McIver; Khalid Mezzi; Phuong Khanh Morrow; Anthony Stein

doi:10.1016/j.blre.2020.100672

Targeting MCL-1 in hematologic malignancies: Rationale and progress

Blood Rev. 2020 Nov:44:100672. doi: 10.1016/j.blre.2020.100672. Epub 2020 Feb 21.

Authors

Affiliations

¹ Alfred Hospital and Monash University, Melbourne, VIC, Australia. Electronic address: Andrew.wei@monash.edu.
² University of Melbourne, Royal Melbourne Hospital, Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
³ Alfred Hospital, Monash University, Australian Centre for Blood Diseases, Melbourne, VIC, Australia.
⁴ University of California Davis School of Medicine, Sacramento, CA, USA.
⁵ John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ, USA.
⁶ Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁷ Amgen Inc., Thousand Oaks, CA, USA.
⁸ Gehr Family Center for Leukemia, City of Hope Medical Center, Duarte, CA, USA.

Abstract

Myeloid cell leukemia sequence 1 (MCL-1) is an antiapoptotic protein that plays a key role in promoting cell survival in multiple myeloma (MM), acute myeloid leukemia (AML), and non-Hodgkin lymphoma (NHL). Overexpression of MCL-1 is associated with treatment resistance and poor prognosis; thus, MCL-1 inhibitors are rational therapeutic options for malignancies depending on MCL-1. Several MCL-1 inhibitors have entered clinical trials, including AZD5991, S64315, AMG 176, and AMG 397. A key area of investigation is whether MCL-1 inhibitors will complement the activity of BCL-2 inhibitors, such as venetoclax, and synergistically enhance anti-tumor efficacy when given in combination with other anti-cancer drugs. Another important question is whether a safe therapeutic window can be found for this new class of inhibitors. In summary, inhibition of MCL-1 shows potential as a treatment for hematologic malignancies and clinical evaluation of MCL-1 inhibitors is currently underway.

Keywords: Acute myeloid leukemia; BH3-mimetic; MCL-1 inhibitor; Multiple myeloma; Non-Hodgkin lymphoma.

Publication types

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

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Gene Expression Regulation, Neoplastic / drug effects
Hematologic Neoplasms / drug therapy
Hematologic Neoplasms / genetics*
Hematologic Neoplasms / metabolism
Humans
Leukemia, Myeloid, Acute / drug therapy
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / metabolism
Molecular Targeted Therapy
Multiple Myeloma / drug therapy
Multiple Myeloma / genetics*
Multiple Myeloma / metabolism
Myeloid Cell Leukemia Sequence 1 Protein / analysis
Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
Myeloid Cell Leukemia Sequence 1 Protein / genetics*
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
Signal Transduction / drug effects
Up-Regulation / drug effects

Substances

Antineoplastic Agents
MCL1 protein, human
Myeloid Cell Leukemia Sequence 1 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding