Journal article
Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers
ST Diepstraten, Y Yuan, JE La Marca, S Young, C Chang, L Whelan, AM Ross, KC Fischer, G Pomilio, R Morris, A Georgiou, V Litalien, FC Brown, AW Roberts, A Strasser, AH Wei, GL Kelly
Cancer Cell | Published : 2024
Abstract
TP53-mutant blood cancers remain a clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins, inducing cancer cell apoptosis. Despite acting downstream of p53, functional p53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report p53 is activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feedforward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 can be overcome by direct acti..
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Grants
Awarded by Cass Foundation
Funding Acknowledgements
We thank WEHI colleagues for support and advice, particularly Elizabeth Lieschke, Yexuan Deng, Margaret Potts, Christina Koenig, Lin Tai, and Marco Herold; Duong Nhu and Guillaume Lessene for A-1331852; WEHI Bioservices, particularly Lauren Wilkins, Natasha Blasch, Natalia MoraTorres and Giovanni Siciliano; the WEHI FACS team and professional services; and the patients who donated their samples for research. This study was supported by the Australian Government NHMRC (GNT1113133 [A.S.] , GNT1116937 [A.S.] , GNT2018071 [A.H.W.] , GNT2002618 [G.L.K.] , GNT2001201 [G.L.K.] , GNT2011139 [G.L.K., A.W.R.,and A.H.W.] , GNT2010275 [A.S.] , GNT1176175 [F.C.B.] , GNT1174902 [A.W.R.] , and GNT2014234 [Y.Y.] ) , Victorian Cancer Agency (17028 [G.L.K.] and 21006 [S.T.D.] ) , MRFF (2023403 [A.H.W.] ) , CASS Foundation (S.T.D. and J.E.L.M.) , estate of Anthony (Toni) Redstone OAM (A.S. and G.L.K.) , Craig Perkins Cancer Research Foundation (G.L.K.) , Dyson Bequest (G.L.K.) , Harry Secomb Foundation (G.L.K.) , Robert and Janette Boffey (J.E.L.M.) , Jill and Stuart Bales (S.T.D.) , Metcalf Family Fellowship (A.H.W.) , RCPA Foundation (Y.Y) , and the Victorian State Government Operational Infrastructure Support and NHMRC Independent Research Institute Infrastructure Support schemes.r and A.H.W.] , GNT2010275 [A.S.] , GNT1176175 [F.C.B.] , GNT1174902 [A.W.R.] , and GNT2014234 [Y.Y.] ) , Victorian Cancer Agency (17028 [G.L.K.] and 21006 [S.T.D.] ) , MRFF (2023403 [A.H.W.] ) , CASS Foundation (S.T.D. and J.E.L.M.) , estate of Anthony (Toni) Redstone OAM (A.S. and G.L.K.) , Craig Perkins Cancer Research Foundation (G.L.K.) , Dyson Bequest (G.L.K.) , Harry Secomb Foundation (G.L.K.) , Robert and Janette Boffey (J.E.L.M.) , Jill and Stuart Bales (S.T.D.) , Metcalf Family Fellowship (A.H.W.) , RCPA Foundation (Y.Y) , and the Victorian State Government Operational Infrastructure Support and NHMRC Independent Research Institute Infrastructure Support schemes.