Oral and Poster Abstracts
603. Oncogenes and Tumor suppressors: Pre clinical models and Novel Targets
Sha Li1*, Anne-Louise Latif2*, Ashley Newcombe2*, Kathryn Gilrory2*, Neil Robertson2*, Xue Lei1*, Darren Finlay3*, Karina Barbosa, BSc1, Helen Stewart4*, John Cole2*, Maria Terradas Terradas2*, Loveena Rishi Delori2*, Lynn McGarry5*, Claire McKeeve6*, Claire Reid2*, William Clark5*, Joana Campos2*, Kristina Kirschner2*, Andrew Davis1*, Jonathan Lopez2*, Jun-Ichi Sakamaki5*, Jennifer Morton2*, Kevin Ryan5*, Stephen Tait2*, Sheela Abraham7*, Tessa L. Holyoake, MD, PhD, FRCP, FRCPath2, Brian Higgins8*, Xu Huang, BSc, PhD2*, Karen Blyth2*, Mhairi Copland, PhD, MBBChir, FRCP, FRCPath2, Timothy Chevassut4*, Aniruddha J. Deshpande, PhD1, Karen Keeshan2* and Peter Adams, PhD1*
1Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
2University of Glasgow, Glasgow, United Kingdom
3Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
4University of Sussex, Brighton, United Kingdom
5Cancer Research UK Beatson Institute, Glasgow, United Kingdom
6Queen Elizabeth University Hospital, Glasgow, United Kingdom
7Queen's University, Ontario, Canada
8Roche Innovation Center, New York
Acute Myeloid Leukemia (AML) is a typically-lethal molecularly heterogeneous disease, with few broad-spectrum therapeutic targets. Unusually compared to many other cancers, over 90% of AML patients retain wild type TP53, encoding pro-apoptotic tumor suppressor p53. However, wild-type p53 functions are frequently suppressed by MDM2, an E3 ubiquitin ligase that targets p53 for proteasomal degradation. MDM2 inhibitors (MDM2i), which activate wild-type p53, show encouraging pre-clinical activity, but limited clinical activity. In an effort to find targets that synergize with p53 activation via MDM2i and minimize toxicity, we performed a cell-based synthetic lethal drug screen and a CRISPR viability screen. These screens identified BRD4 inhibition as a candidate synthetic lethal partner of MDM2i. BRD4 is a member of the Bromodomains and Extraterminal (BET) family of proteins, a transcriptional co-activator and already a candidate AML therapeutic target. Surprisingly, we found inhibition of BRD4 alone induces expression of some of p53 target genes. We unexpectedly reveal that BRD4 binds to p53 target genes and acts as a transcriptional repressor of these genes. Synergistic cell killing by the drug combination (MDM2i + BET inhibitor (BETi)) depends on synergistic activation of p53 target genes, such as PUMA and NOXA, due to simultaneous stabilization of p53 by MDM2i and relief of BRD4-mediated repression by BETi. Our combined therapy of MDM2i and BETi is synergistically lethal to human AML cell lines harboring wild type TP53 in vitro, against two mouse models of AML in vivo, and against primary human patient blasts in vitro. Furthermore, we used BET PROTACs to selectively and completely induce degradation of BRD4 in cells. Consistent with results from BETi, BET degraders and MDM2i synergize to suppress cell viability with superior potency. Taken together, our data show BRD4 represses p53-mediated transcription activation and apoptosis in AML. Therefore, co-targeting wild-type TP53 and a transcriptional repressor function of BRD4 represent a novel synthetic lethal vulnerability in AML.
*signifies non-member of ASH
Disclosures: Latif: AbbVie: Consultancy, Honoraria; Takeda UK: Speakers Bureau; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria. Higgins: Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Copland: Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Cyclacel Ltd: Research Funding; Roche: Research Funding; Epizyme: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau; Gilead: Speakers Bureau.