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 Reljic; 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; Sebastien Banquet; Ian J Majewski; Andreas Strasser; Andrew W Roberts; David CS Huang; Fiona C Brown; Gemma L Kelly; Andrew H Wei

Journal article

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 Reljic, Sarah S Gabriel, Tirta M Djajawi, Chris D Riffkin, Brandon J Aubrey, Catherine Chang, Lin Tai, Zhen Xu, Thomas Morley Show all

BLOOD | AMER SOC HEMATOLOGY | Published : 2021

DOI: 10.1182/blood.2020010167

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. Str..

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University of Melbourne Researchers

Axel Kallies Author Microbiology and Immunology

Andreas Strasser Author Medical Biology (w.e.h.i.)

Ian Majewski Author Medical Biology (w.e.h.i.)

Gemma Kelly Author Medical Biology (w.e.h.i.)

Ruth Kluck Author Medical Biology (w.e.h.i.)

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Grants

Awarded by Australian National Health andMedical Research Council (NHMRC)

Awarded by Leukemia and Lymphoma Society of America

Awarded by Specialized Center of Research [SCOR] grant

Awarded by Cure Cancer and Cancer Australia

Awarded by Victorian Cancer Agency (Mid-career Research Fellowship [MCRF])

Awarded by MCRF Fellowship

Awarded by Cancer Council Victoria

Awarded by Swiss National Science Foundation

Awarded by Medical Research Future Fund

Awarded by Tour de Cure Foundation

Funding Acknowledgements

This work was supported by fellowships and grants from the Australian National Health andMedical Research Council (NHMRC; Program Grants 1016701 [R.M.K., A.S., and D.C.S.H.] and 1113577 [A.W.R.]; Research Fellowships 1139607 [A.K.], 1140851 [D.A.S.], 1020363 [A. S.], 1079560 [A.W.R.], and 1156024 [D.C.S.H.]; Investigator G rants 1176175 [F.C.B.], 1174902 [A.W.R.], and 1157263 [C.B.]; Project Grants 1140906 [D.A.S.], 1162809 [A.H.W.], and 1086291 [G.L.K.]; and Ideas Grants 2002618 and 2001201 [G.L.K.]); the Leukemia and Lymphoma Society of America (Fellowship 5467-18 [R.T.]; Specialized Center of Research [SCOR] grant 7015-18 (R.M.K., A.S., A.W.R., A.H.W., G.L.K., and D.C.S.H.); a Cure Cancer and Cancer Australia grant (1186003 [R.T.]); Victorian Cancer Agency (Mid-career Research Fellowship [MCRF] 17028 [G.L.K.], MCRF Fellowship 19011 [D.M.M.], and grant 15018 [I.J.M., A.W.R., and A.H.W.); Cancer Council Victoria grants-in-aid 1086157 and 1147328 (G.L.K.), 1124178 (I.J.M.), and 1141740 (D.M.M.); Leukaemia Foundation of Australia (the Bill Long Charitable Trust PhDClinical Scholarship [E.C., A.S., and G.L.K.]); fellowships from Novartis Foundation for Medical-Biological Research and the Swiss National Science Foundation (P400PM-180807 [S.S.G.]); the Felton Bequest (I.J.M.); the estate of Anthony (Toni) Redstone OAM (A.S. and G.L.K.); the Craig Perkins Cancer Research Foundation (G.L.K.); the Dyson Bequest (G.L.K.); Medical Research Future Fund grant 1141460 (A.H.W.); Tour de Cure Foundation (RSP212-2020); and the Australian Cancer Research Foundation. This work was made possible through Victorian State Government Operational Infrastructure Support (OIS) and Australian Government NHMRC Independent Research Institute Infrastructure Support (IRIIS) Scheme.