Therapeutic Targeting of EP300/CBP By Bromodomain Inhibition in Acute Myeloid Leukemia

Nicosia, Luciano; Spencer, Gary J.; Brooks, Nigel; Amaral, Fabio; Basma, Naseer J.; Chadwick, John; Revell, Bradley; Wingelhofer, Bettina; Maiques-Díaz, Alba; Ciceri, Filippo; Pegg, Neil; West, William H.; Knurowski, Tomasz; Frese, Kris; Clegg, Karen; Campbell, Victoria; Copland, Mhairi; Searle, Emma; Somervaille, Tim C. P.

doi:10.1182/blood-2022-166260

Cited by 9 publications

(11 citation statements)

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“…S5D; refs. 45–47 ). Flow-cytometric analysis of drug-treated HMCLs revealed that the POM + G781 combination significantly reduced myeloma cell numbers and increased apoptosis and cell death in vitro compared with POM or G781 individually ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

Welsh,

Barwick,

Meermeier

et al. 2023

Blood Cancer Discovery

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Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiDs). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance.

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Section: Resultsmentioning

confidence: 99%

Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

Welsh,

Barwick,

Meermeier

et al. 2023

Blood Cancer Discovery

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“…Bone marrow neutrophils from 2208L and PyMT-N tumor-bearing mice were shown to suppress T-cell activation in vivo (Casbon et al, 2015, Kim et al, 2019). CBP/P300 BRD inhibition has been shown to reprogram acute myeloid leukemia and myeloma cells in the bone marrow (Nicosia et al, 2023). Abnormal proliferation is a shared characteristic between hematological malignancies and neutrophil overproduction caused by neutrophil-enriched TNBC.…”

Section: Discussionmentioning

confidence: 99%

“…CBP/P300 BRD inhibition has been reported to reprogram cancer cells to reduce proliferation and treatment resistance in many cancer types, but most studies and clinical trials have focused on blood cancers and prostate cancer (Chen et al, 2022, Nicosia et al, 2023, Raisner et al, 2018, Jin et al, 2017). For TNBC, CBP/P300 BRD inhibition has been shown to reduce the growth of patient-derived androgen receptor-positive TNBC xenografts and MDA-MB-231 xenografts (Caligiuri et al, 2023, de Almeida Nagata et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…The BRD of CBP/P300 is involved in the positive feedback of histone acetylation and transcription activation (Das et al, 2014, Kikuchi et al, 2023). CBP/P300 BRD inhibitor CCS147 is in clinical trials for hematologic malignancies (Nicosia et al, 2023, Raisner et al, 2018). More importantly, inhibition of P300/CBP BRD was able to reduce the growth of a human TNBC xenograft model MDA-MB-231 X1.1 and reprogrammed the tumor-associated myeloid cells (de Almeida Nagata et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

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CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC

Yuan,

Hao,

Chan

et al. 2024

Preprint

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Tumor-associated neutrophils (TANs) have been shown to promote immunosuppression and tumor progression, and a high TAN frequency predicts poor prognosis in triple-negative breast cancer (TNBC). Dysregulation of CREB binding protein (CBP)/P300 function has been observed with multiple cancer types. The bromodomain (BRD) of CBP/P300 has been shown to regulate its activity. In this study, we found that IACS-70654, a novel and selective CBP/P300 BRD inhibitor, reduced TANs and inhibited the growth of neutrophil-enriched TNBC models. In the bone marrow, CBP/P300 BRD inhibition reduced the tumor-driven abnormal differentiation and proliferation of neutrophil progenitors. Inhibition of CBP/P300 BRD also stimulated the immune response by inducing an IFN response and MHCI expression in tumor cells and increasing tumor-infiltrated CTLs. Moreover, IACS-70654 improved the response of a neutrophil-enriched TNBC model to docetaxel and immune checkpoint blockade. This provides a rationale for combining a CBP/P300 BRD inhibitor with standard-of-care therapies in future clinical trials for neutrophil-enriched TNBC.

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“…Determining mechanisms to directly antagonize CBP/p300 function in the clinical setting may also be an important next avenue of investigation. Currently, ongoing clinical trials to determine the efficacy and tolerability of CCS1477 (Inobrodib) include evaluation in solid tumors (clinical trial identifier NCT03568656) and hematological malignancies 107 . Specifically, an open label phase I/IIa study of CCS1477 as monotherapy and in combination with AR targeting agents will lead to more insight for the role of HRD impacting efficacy.…”

Section: Discussionmentioning

confidence: 99%

AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer

Sardar,

McNair,

Ravindranath

et al. 2024

Preprint

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Castration resistant prostate cancer (CRPC) remains an incurable disease stage with ineffective treatments options. Here, the androgen receptor (AR) coactivators CBP/p300, which are histone acetyltransferases, were identified as critical mediators of DNA damage repair (DDR) to potentially enhance therapeutic targeting of CRPC. Key findings demonstrate that CBP/p300 expression increases with disease progression and selects for poor prognosis in metastatic disease. CBP/p300 bromodomain inhibition enhances response to standard of care therapeutics. Functional studies, CBP/p300 cistrome mapping, and transcriptome in CRPC revealed that CBP/p300 regulates DDR. Further mechanistic investigation showed that CBP/p300 attenuation via therapeutic targeting and genomic knockdown decreases homologous recombination (HR) factorsin vitro,in vivo, and in human prostate cancer (PCa) tumorsex vivo. Similarly, CBP/p300 expression in human prostate tissue correlates with HR factors. Lastly, targeting CBP/p300 impacts HR-mediate repair and patient outcome. Collectively, these studies identify CBP/p300 as drivers of PCa tumorigenesis and lay the groundwork to optimize therapeutic strategies for advanced PCa via CBP/p300 inhibition, potentially in combination with AR-directed and DDR therapies.

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Therapeutic Targeting of EP300/CBP By Bromodomain Inhibition in Acute Myeloid Leukemia

Cited by 9 publications

References 0 publications

Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma

CBP/P300 BRD Inhibition Reduces Neutrophil Accumulation and Activates Antitumor Immunity in TNBC

AR coactivators, CBP/p300, are critical mediators of DNA repair in prostate cancer

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