Vulnerability of Small-Cell Lung Cancer to Apoptosis Induced by the Combination of BET Bromodomain Proteins and BCL2 Inhibitors

Abstract

Ten percent to 15% of all lung cancers are small-cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extraterminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis, such as , and Here, we demonstrate that approximately 50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075. The majority of these SCLC cell lines underwent apoptosis in response to ABBV-075 treatment via induction of caspase-3/7 activity. ABBV-075 enhanced the expression of proapoptotic protein BIM and downregulated antiapoptotic proteins BCL2 and BCLxl to a lesser extent. Furthermore, BET inhibition increased BCL2-BIM complex, thus priming the cells for apoptosis. Indeed, strong synergy was observed both and when cotreating the cells with BET inhibitor and the BH3-mimetic, BCL2 inhibitor venetoclax (ABT-199). ABBV-075 interaction with venetoclax positively correlated with BCL2 expression. Taken together, our studies provide a rationale for treating SCLC with BET and BCL2 inhibitors in tumors with high BCL2 protein expression. .

BET-inhibitors as sensitizers for BH3-mimetics

“…However, additional more detailed studies, for instance in orthotopic xenografts, are necessary to judge the overall impact. Our findings are supported by other groups, showing similar findings in other tumor entities, involving the selective Bcl-2 inhibitor, ABT199 [7, 8] which recently was designated for accelerated FDA approval. All in all, the combination treatment of BH3-mimetics and BET-inhibitors appears to be a potential treatment strategy for several malignancies and should be explored further.…”

Venetoclax Is Effective in Small-Cell Lung Cancers with High BCL-2 Expression

“…In addition, Lam et al very recently reported that venetoclax sensitizes SCLC cell lines to BET inhibition (33). These previous reports support the potential of venetoclax in SCLC.…”

Family matters: How MYC family oncogenes impact small cell lung cancer

“…127 JQ-1 was moreover shown to have antiproliferative effects in SCLC cell lines. 128,129 Interestingly, key targets with reduced expression upon JQ-1 treatment in SCLC cell lines were MYC family members 129 and ASCL1, 130 but currently biomarkers predicting JQ-1 sensitivity in SCLC are lacking. More recently, CHK1 inhibition has been identified as an additional drug target that elicits efficacy specifically in MYCdriven SCLC, 11 suggesting that MYC status is an important determinant of therapeutic response in SCLC.…”