Targeting BET and Kinases: A Dual Approach to Overcoming Multiple Myeloma

The BET proteins, which include c-Myc, play a crucial role in the regulation of cancer-related genes. JQ1, a potent BRD4 inhibitor, has shown effectiveness in clinical trials for multiple myeloma, but resistance has been a concern. To address this, a new class of dual inhibitors has been developed, targeting not only BRD4 but also tyrosine kinases that are frequently overexpressed in cancer. SG3-014 emerged as a promising candidate with comparable inhibitory activity to JQ1 against BRD4 and c-Myc, while also inhibiting cancer-associated kinases implicated in drug resistance.

Laboratory tests on multiple myeloma cell lines indicated that SG3-014 demonstrated greater sensitivity than JQ1. Animal studies further supported the potential of SG3-014, showing improved survival rates and a reduction in myeloma-induced bone disease in treated mice. Examination of clinical data identified ULK3 as a key target of SG3-014, with its expression linked to disease progression. Given ULK3's role in cellular processes that protect cancer cells from apoptosis, the impact of SG3-014 on the autophagy pathway was investigated.

Initial findings indicate that SG3-014 inhibits autophagy, reducing levels of key proteins and disrupting autophagosome formation, an effect not observed with JQ1. Further research is underway to understand how SG3-014's inhibition of ULK3 contributes to cancer cell death via autophagy. Future work will involve analyzing patient samples and assessing the inhibitor's effectiveness in patient-derived multiple myeloma cells.

The study suggests that a dual approach targeting BRD4 and autophagy could be a robust strategy to combat multiple myeloma and circumvent resistance to single-target therapies.