Flash Talk + Poster Presentation 38th Lorne Cancer Conference 2026

p300/CBP co-ordinate with the metazoan INO80 complex in haematological malignancies, providing synthetic lethal opportunities.  (#202)

Oliver Sinclair 1 2 , Jesse Balic 1 , Andrea Gillespie 1 , Tim Somervaille 2 , Mark Dawson 1
  1. Peter MacCallum Cancer Centre, Brunswick, VIC, Australia
  2. CRUK MI, Manchester

Following successful collaboration between Cancer Research UK Manchester Institute and the UK-based biotech company CellCentric, Prof. Tim Somervaille and Oliver Sinclair have led preclinical and early-phase clinical evaluation of inobrodib (CCS1477; herein CCS). CCS is a first-in-class, potent, selective, orally bioavailable bromodomain inhibitor of the p300/CBP histone acetyltransferases with objective and durable clinical responses in acute myeloid leukaemia (AML) and multiple myeloma (MM)(1).

While AML and MM are distinct diseases, they share common features such as pre-malignant clonal outgrowth and mutational burden in transcriptional regulators. The result is a shared dependency on transcription factors (TFs) and enhancer-mediated regulation of oncogenic programs. This process is orchestrated by p300/CBP which provides a therapeutic window. However, clinical trial data demonstrated significant heterogeneity in response to CCS: while some patients respond well, many do not, highlighting the critical unmet need to identify synthetic lethal targets that enhance efficacy.

To address this challenge, we have conducted high-coverage CRISPR/Cas9 screens in several AML and MM cell lines to identify genes governing CCS sensitivity or resistance. These screens have yielded both expected and novel findings. Consistent with previous observations that CBP-inactivating mutations sensitise lymphoma cells to p300/CBP inhibition, we found that genetic deletion of either P300 or CBP enhanced CCS sensitivity (2). Additionally, we identified the HDAC3-NCoR complex, a known antagonist of p300/CBP, as a driver of resistance (3).

Crucially, we discovered that multiple components (INO80E, INO80D, NFRKB, UCHL5, TFPT) of the metazoan-specific INO80 (mINO80) complex are key mediators of CCS sensitivity when knocked out.

To further investigate this synthetic lethal vulnerability between p300/CBP inhibtion and mIN080 loss, we developed an epitope-coupled dTAG system in the MM line OPM2. Here, we fused both a ligand-responsive degron (dTAG) and an affinity tag to mINO80 subunits, enabling the first insights into genome occupancy of the mINO80 complex. ChIP-seq analyses revealed a significant co-localisation of mINO80 and p300 at oncogenic driver genes known to be perturbed by CCS treatment of MM cells, such as IRF4, the central TF that drives MM.

Together, these findings suggest a novel synthetic lethal therapeutic approach to target the mINO80 complex in combination with CCS.

  1. Nicosia L, Spencer GJ, Brooks N, Amaral FM, Basma NJ, Chadwick JA, et al. Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies. Cancer Cell. 2023;41(12):2136-53. e13.
  2. Meyer SN, Scuoppo C, Vlasevska S, Bal E, Holmes AB, Holloman M, et al. Unique and shared epigenetic programs of the CREBBP and EP300 acetyltransferases in germinal center B cells reveal targetable dependencies in lymphoma. Immunity. 2019;51(3):535-47. e9.
  3. Hogg SJ, Motorna O, Cluse LA, Johanson TM, Coughlan HD, Raviram R, Myers RM, Costacurta M, Todorovski I, Pijpers L, Bjelosevic S. Targeting histone acetylation dynamics and oncogenic transcription by catalytic P300/CBP inhibition. Molecular cell. 2021 May 20;81(10):2183-200.