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This article determines if patient, defect, and repair factors can be used to predict the use of additional treatments to achieve optimal aesthetic results after repair of facial Mohs defects. An electronic chart review of patients undergoing Mohs excision and reconstruction of facial neoplasms from November 2005 to April 2017 was performed, reviewing patient demographics and history, tumor size, defect size and location, method and service of reconstruction, time between resection and repair, complications, and subsequent treatments. A total of 1,500 cases with basal cell and squamous cell carcinoma were analyzed. The average defect size was 3.09 ± 8.06 cm2; 81.9% of defects were less than 4 cm2 in size. Advancement flaps were used to repair 44.3% of defects. Complications and undesired sequelae (CUS) were noted in 15.9% of cases; scar hypertrophy or keloid (10.8%) was most common. Postoperative ancillary procedures were performed in less than one-quarter (23.4%) of patients to enhance the postrepair appearance; the most common procedures were intralesional corticosteroid injections and pulse dye laser treatments. CUS were more likely in females (19.6%), defects on the lips (28.7%) and on the nose (27.3%) (p < 0.001 for each). Females (22.7% vs. 12.7%), lip repairs (40.2% vs. 18.3%), transposition flaps (39.2% vs. 14.8%), and repairs performed by a dermatologist (17.9% vs. 11.2%) (p < 0.001 for each) were more likely to be treated with postoperative corticosteroid injections. Females (14.5% vs. 7.4%), patients under the age of 60 years (13.9% vs. 8.8%), and patients whose repair was performed by a dermatologist (11.9% vs. 2.9%) (p < 0.001 for each) were more likely to receive postoperative pulsed dye laser treatments. CUS and ancillary procedures after repair of facial Mohs defects are uncommon. Awareness of individual risk factors and defect characteristics allows the surgeon to choose the most appropriate repair technique while anticipating the potential need for ancillary procedures.

The chromatin regulators CREB-binding protein (CBP) and p300 are factors critical for establishing and activating enhancer-mediated transcription. These large proteins are made up of at least ten distinct functional domains and are known to interact with over 400 other proteins including DNA-binding transcription factors, other chromatin regulators, and components of the general transcription apparatus. In addition to mediating protein-protein interactions on chromatin, p300/CBP exert enzymatic activity through a lysine acetyltransferase (KAT) domain. p300/CBP can dynamically acetylate ~21,000 lysines on over 5,000 proteins including more than three dozen known enhancer-associated regulators. In cancer, p300/CBP have been implicated as both oncogenes and tumor suppressors in a large number of malignant cell types and active drug development projects by a number of groups have focused on the discovery of potent and selective compounds. Small molecules that target the p300/CBP bromodomain and KAT domains have provided a unique toolset for chromatin and chemical biologists to probe various p300/CBP functions at enhancers. However, it is clear that simultaneous inhibition of multiple functional domains, or even complete protein depletion, is required to ablate the enhancer activity mediated by p300/CBP. To pursue this goal further and to provide the research community with additional tools to probe the function of this important class of chromatin regulators, we have designed and characterized the first heterobifunctional chemical degrader of p300/CBP, dCBP-1. Bifunctional, or chimeric, degraders that leverage the activity of E3 ligases such as cereblon (CRBN) through chemical-induced proximity to proteins of interest have transformed the capabilities for chemical degradation. Aided by in silico modeling of a ternary complex of ligand-bound CRBN with the KAT and bromodomains of p300/CBP, we were able to efficiently synthesize a highly potent and selective degrader, dCBP-1. Using dCBP-1 as a tool, we profile the consequences of complete p300/CBP loss in cellular models of multiple myeloma, a tumor type uniquely addicted to the activity of both p300 and CBP. Proteomics profiling reveals selective effects on p300 and CBP, with loss of oncogenic MYC expression. Epigenomic profiles of gene expression and chromatin structures with dCBP-1 treatment reveals augmented effects of oncogene expression compared to inhibitors alone or in combination, with complete ablation of histone lysine acetylation and chromatin accessibility at enhancers, including the immunoglobulin locus enhancer that can drive oncogenic MYC expression in ~20% of multiple myeloma. Taken together, dCBP-1 is the first rapid potent and selective chemical degrader of p300/CBP and enables pharmacologic disruption of p300/CBP-regulated enhancers. Citation Format: Samuel Ojeda, Raghu Vannam, Jan Sayilgan, Barbara Karakyriakou, Eileen Hu, Johannes Kreuzer, Robert Morris, Xcanda Ixchel Herrera Lopez, Sumit Rai, Wilhelm Haas, Michael Lawrence, Christopher J. Ott. Targeted degradation of the enhancer lysine acetyltransferases CBP and p300 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1146.