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  3. Reduced Mitochondrial Apoptotic Priming Drives Resistance to BH3 Mimetics in Acute Myeloid Leukemia

Reduced Mitochondrial Apoptotic Priming Drives Resistance to BH3 Mimetics in Acute Myeloid Leukemia

  • Cancer Cell. 2020 Dec 14;38(6):872-890.e6. doi: 10.1016/j.ccell.2020.10.010.
Shruti Bhatt 1,  Marissa S Pioso 2,  Elyse Anne Olesinski 2,  Binyam Yilma 2,  Jeremy A Ryan 2,  Thelma Mashaka 2,  Buon Leutz 3,  Sophia Adamia 4,  Haoling Zhu 4,  Yanan Kuang 3,  Abhishek Mogili 3,  Abner Louissaint Jr 4,  Stephan R Bohl 2,  Annette S Kim 5,  Anita K Mehta 6,  Sneha Sanghavi 7,  Youzhen Wang 7,  Erick Morris 7,  Ensar Halilovic 7,  Cloud P Paweletz 8,  David M Weinstock 2,  Jacqueline S Garcia 4,  Anthony Letai 9
Affiliations

Affiliations

  • 1 Department of Medical Oncology, Dana-Farber Cancer Institute, 440 Brookline Avenue, M430, Boston, MA 02215, USA; Harvard Medical School, Boston, MA, USA; Department of Pharmacy, National University of Singapore, Singapore.
  • 2 Department of Medical Oncology, Dana-Farber Cancer Institute, 440 Brookline Avenue, M430, Boston, MA 02215, USA; Harvard Medical School, Boston, MA, USA.
  • 3 Department of Bioinformatics and Data Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, 440 Brookline Avenue, M430, Boston, MA 02215, USA.
  • 5 Harvard Medical School, Boston, MA, USA; Brigham and Women's Hospital, Boston, MA, USA.
  • 6 Breast Tumor Immunology Laboratory, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 7 Novartis Institutes for BioMedical Research, Inc., Cambridge, MA, USA.
  • 8 Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 9 Department of Medical Oncology, Dana-Farber Cancer Institute, 440 Brookline Avenue, M430, Boston, MA 02215, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: anthony_letai@dfci.harvard.edu.
PMID: 33217342 DOI: 10.1016/j.ccell.2020.10.010
Abstract

Acquired resistance to BH3 mimetic antagonists of Bcl-2 and Mcl-1 is an important clinical problem. Using acute myelogenous leukemia (AML) patient-derived xenograft (PDX) models of acquired resistance to Bcl-2 (venetoclax) and Mcl-1 (S63845) antagonists, we identify common principles of resistance and persistent vulnerabilities to overcome resistance. BH3 mimetic resistance is characterized by decreased mitochondrial apoptotic priming as measured by BH3 profiling, both in PDX models and human clinical samples, due to alterations in Bcl-2 Family proteins that vary among cases, but not to acquired mutations in leukemia genes. Bcl-2 inhibition drives sequestered pro-apoptotic proteins to Mcl-1 and vice versa, explaining why in vivo combinations of Bcl-2 and Mcl-1 antagonists are more effective when concurrent rather than sequential. Finally, drug-induced mitochondrial priming measured by dynamic BH3 profiling (DBP) identifies drugs that are persistently active in BH3 mimetic-resistant myeloblasts, including Flt-3 inhibitors and SMAC mimetics.

Keywords

BCL-2; BH3 mimetics; BH3 profiling; FLT-3; MCL-1; SMAC; leukemia; mitochondria; precision cancer medicine; venetoclax.

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