Abstract (eng)
Esophageal squamous cell carcinoma (ESCC) is the most prevalent type of esophageal cancer which is the sixth leading cause of deaths due to cancer worldwide, with a five-year survival rate of 15-25%. Therapy options are limited due to the aggressive nature of the disease and late diagnosis, accompanied with the presence of distant metastasis. Next generation sequencing has allowed the identification of gene mutations in diverse cancer subtypes thereby defining oncogenes as well as tumor suppressor genes. As a result, patients with an oncogenic “driver” mutation can therefore be treated by targeted therapy, exploiting the protein alteration. In contrast, reconstituting a tumor suppressor is (currently) therapeutically not feasible. However, this can be circumvented by harnessing the concept of synthetic lethality. By inhibiting the functional redundant partner, tumor growth can be impaired whereby sparing other cell types of the human body. In wild-type cells, the synthetic lethal factor is still present, which compensates for the loss of the individual partner. CRISPR-Cas9 screens targeting specific domains within the epigenome, were conducted with the aim to identify novel targets in ESCC. SMARCA4, the catalytic subunit of the chromatin remodeling complex SWI/SNF (BAF), was identified as a strong hit which exclusively scored in cell lines with SMARCA2low (mutual exclusive ATPase) background indicating synthetic lethal dependencies. Rescue experiments confirmed the importance of the ATPase-domain of SMARCA4 for cell survival. The paralog dependency could be highlighted by either re-expression of SMARCA2 in SMARCA2low cell lines, reverting the dependency, or by knocking-out SMARCA2 in SMARCA2-proficient cell lines, transforming them into SMARCA4-dependent ones. In addition, cell lines from different indications including colon, pancreas, and ovarian carcinoma were identified as SMARCA2low and SMARCA4-dependent, which might allow for extension of the therapeutic concept to additional indications with a defined patient selection biomarker (SMARCA2low). To date, no selective SMARCA4 inhibitors are available. Therefore, a domain-swap strategy was used, exchanging the bromodomain of SMARCA4, with the one of BRD9. This allowed pharmacological inhibition of chimeric SMARCA4 by using a BRD9 bromodomain directed PROTAC (dBRD9). Targeted degradation as well as impaired viability and thereby confirms SMARCA4 as a potential target in SMARCA2low ESCC.