ADVERTISEMENT
Therapeutic Targeting of BAP1/ASXL3 Sub-Complex in SCLC
Investigators sought to discover the function of the oncogenic BAP1/ASXL3/BRD4 epigenetic axis in small-cell lung cancer (SCLC) by developing a next-generation BAP1 inhibitor, iBAP-II. While keeping in mind discovering and targeting functional biomarkers for SCLC is crucial in understanding the molecular basis underlying tumorigenesis to better assist in improving clinical treatment, investigators focused on the epigenetic balance established between BAP1 and non-canonical PRC1 complexes in regulating SCLC-specific transcriptional programming.
“We further demonstrated that pharmacologic inhibition of BAP1's catalytic activity disrupted BAP1/ASXL3/BRD4 epigenetic axis by inducing protein degradation of the ASXL3 scaffold protein, which bridges BRD4 and BAP1 at active enhancers,” investigators explained.
Additionally, iBAP-II therapy is known to repress neuroendocrine lineage-specific ASCL1/MYCL/E2F signaling in SCLC cell lines, and noted to dramatically inhibit SCLC cell viability and tumor growth in vivo.
“In summary, this study has provided mechanistic insight into the oncogenic function of BAP1 in SCLC and highlighted the potential of targeting BAP1's activity as a novel SCLC therapy,” investigators concluded.
Resource
Tsuboyama N, Wang R, Szczepanski AP, et al. Therapeutic targeting of BAP1/ASXL3 sub-complex in ASCL1-dependent small cell lung cancer [published online ahead of print, 2022 Feb 22]. Oncogene. 2022;10.1038/s41388-022-02240-x. doi:10.1038/s41388-022-02240-x
