Pharmacological inhibition of CBP sensitizes breast cancer to DNA-damaging agents by compromising DNA repair and cell cycle pathways.

Authors

Wafaa S Ramadan, Iman M Talaat, Aya Mudhafar Al-Azawi, Nadine Ibrahim, Sara Al-Sherief, Shahenaz S Salih, Rawia Mohamed, Basma M Sharaf, Mohammad H Semreen, Fatema Hersi, Hany A Omar, Raafat El-Awady

Published in

Translational research : the journal of laboratory and clinical medicine. Sep 06, 2026. Epub Sep 06, 2026.

Abstract

Chemotherapy remains central to breast cancer treatment, particularly for aggressive subtypes like triple-negative breast cancer. Despite its widespread use, the toxicity of chemotherapeutic agents and frequent resistance limit clinical success. Epigenetic therapy offers a promising translational approach due to its reversible modulation of gene expression via histone and non-histone modifications that regulate key signaling pathways, including those involved in DNA repair. CREB-binding protein (CBP), a key histone acetyltransferase, is involved in ATM activation, a central component of the DNA damage response. The loss of CBP was found to sensitize breast cancer cells to chemo- and radiotherapy, thereby identifying CBP as a potential therapeutic vulnerability. In the present study, we investigated the proteomic consequences of pharmacological inhibition of CBP in breast cancer cells using two domain-specific inhibitors, C646 (HAT domain) and inobrodib (bromodomain), and assessed their translational potential in combination with doxorubicin. Using in vitro and in vivo breast cancer models, we showed that CBP inhibition disrupts DNA repair and cell-cycle regulatory pathways, thereby enhancing doxorubicin-induced cytotoxicity and apoptosis. Interestingly, the combination groups displayed the most pronounced effects on tumor growth and showed elevated levels of cleaved caspase-3, while suppression of ki67 expression and H3K27 acetylation. Additionally, the combination of CBP inhibitors with doxorubicin did not affect the body weight or the organ indices. These findings support a rational epigenetic-chemotherapy combination approach and provide preliminary preclinical evidence for further investigation of CBP-targeted strategies to improve chemotherapy efficacy while mitigating toxicity.

PMID:
42702301
Bibliographic data and abstract were imported from PubMed on 07 Sep 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.