Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias

Rachel Thijssen; Sarah T Diepstraten; Donia Moujalled; Edward Chew; Christoffer Flensburg; Melissa X Shi; Michael A Dengler; Veronique Litalien; Sarah MacRaild; Maoshan Chen; Natasha S Anstee; Boris Reljić; Sarah S Gabriel; Tirta M Djajawi; Chris D Riffkin; Brandon J Aubrey; Catherine Chang; Lin Tai; Zhen Xu; Thomas Morley; Giovanna Pomilio; Claudia Bruedigam; Axel Kallies; David A Stroud; Ashish Bajel; Ruth M Kluck; Steven W Lane; Marie Schoumacher; Sébastien Banquet; Ian J Majewski; Andreas Strasser; Andrew W Roberts; David C S Huang; Fiona C Brown; Gemma L Kelly; Andrew H Wei

doi:10.1182/blood.2020010167

Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias

Blood. 2021 May 20;137(20):2721-2735. doi: 10.1182/blood.2020010167.

Authors

Rachel Thijssen^{1

2}, Sarah T Diepstraten^{1

2}, Donia Moujalled³, Edward Chew^{1

2

4

5}, Christoffer Flensburg^{1

2}, Melissa X Shi¹, Michael A Dengler^{1

2

6}, Veronique Litalien³, Sarah MacRaild⁷, Maoshan Chen³, Natasha S Anstee^{3

7}, Boris Reljić^{8

9}, Sarah S Gabriel¹⁰, Tirta M Djajawi¹, Chris D Riffkin¹, Brandon J Aubrey^{1

2}, Catherine Chang¹, Lin Tai¹, Zhen Xu^{1

2}, Thomas Morley³, Giovanna Pomilio³, Claudia Bruedigam^{11

12}, Axel Kallies¹⁰, David A Stroud⁸, Ashish Bajel⁴, Ruth M Kluck^{1

2}, Steven W Lane^{11

12}, Marie Schoumacher¹³, Sébastien Banquet¹³, Ian J Majewski^{1

2}, Andreas Strasser^{1

2}, Andrew W Roberts^{1

2

4

6}, David C S Huang^{1

2}, Fiona C Brown³, Gemma L Kelly^{1

2}, Andrew H Wei^{3

8}

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
² Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia.
³ Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia.
⁴ Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
⁵ Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
⁶ Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
⁷ Department of Clinical Haematology, The Alfred Hospital, Melbourne, VIC, Australia.
⁸ Department of Biochemistry and Molecular Biology, The Bio21 Institute, University of Melbourne, Melbourne, VIC, Australia.
⁹ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia.
¹⁰ The Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, University of Melbourne, Melbourne, VIC, Australia.
¹¹ Cancer Program, Queensland Institute of Medical Research (QIMR) Berghofer Medical Research Institute, Brisbane, QLD, Australia.
¹² School of Medicine, University of Queensland, Brisbane, QLD, Australia; and.
¹³ Institut de Recherches Internationales Servier Oncology R&D Unit, Suresnes, France.

Abstract

Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are individually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacology*
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects*
Apoptosis / physiology
Apoptosis Regulatory Proteins / antagonists & inhibitors*
Apoptosis Regulatory Proteins / physiology
Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
CRISPR-Cas Systems
Cell Line, Tumor
DNA Damage
Genes, p53
Humans
Indolizines / pharmacology*
Indolizines / therapeutic use
Interleukin-2 Receptor alpha Subunit / deficiency
Isoquinolines / pharmacology*
Isoquinolines / therapeutic use
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
Leukemia, Myeloid, Acute / drug therapy*
Leukemia, Myeloid, Acute / pathology
Leukemia, Myeloid, Acute / therapy
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Morpholines / pharmacology*
Morpholines / therapeutic use
Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
Neoplasm Proteins / antagonists & inhibitors
Neoplasm Proteins / physiology*
Oxidative Phosphorylation / drug effects
Peptide Fragments / antagonists & inhibitors*
Proto-Oncogene Proteins / antagonists & inhibitors*
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
Sulfonamides / administration & dosage
Sulfonamides / pharmacology*
Sulfonamides / therapeutic use
Tumor Suppressor Protein p53 / deficiency
Tumor Suppressor Protein p53 / physiology*
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Apoptosis Regulatory Proteins
BCL2 protein, human
Bax protein (53-86)
Bridged Bicyclo Compounds, Heterocyclic
Il2ra protein, mouse
Indolizines
Interleukin-2 Receptor alpha Subunit
Isoquinolines
MCL1 protein, human
Morpholines
Myeloid Cell Leukemia Sequence 1 Protein
Neoplasm Proteins
Peptide Fragments
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-bcl-2
S55746
Sulfonamides
TP53 protein, human
Tumor Suppressor Protein p53
venetoclax