Abstract
Non-small cell lung cancer (NSCLC) has the highest incidence of cancer-related death worldwide and a high medical need for more effective therapies. Small-molecule inhibitors of the bromodomain and extra terminal domain (BET) family such as JQ1, I-BET762 and OTX-015 are active in a wide range of different cancer types, including lung cancer. Although their activity on oncogene expression such as c-Myc has been addressed in many studies, the effects of BET inhibition on the apoptotic pathway remain largely unknown. Here we evaluated the activity of BET bromodomain inhibitors on cell cycle distribution and on components of the apoptosis response. Using a panel of 12 KRAS-mutated NSCLC models, we found that cell lines responsive to BET inhibitors underwent apoptosis and reduced their S-phase population, concomitant with downregulation of c-Myc expression. Conversely, ectopic c-Myc overexpression rescued the anti-proliferative effect of JQ1. In the H1373 xenograft model, treatment with JQ1 significantly reduced tumor growth and downregulated the expression of c-Myc. The effects of BET inhibition on the expression of 370 genes involved in apoptosis were compared in sensitive and resistant cells and we found the expression of the two key apoptosis regulators FLIP and XIAP to be highly BET dependent. Consistent with this, combination treatment of JQ1 with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or the pro-apoptotic chemotherapeutic agent cisplatin enhanced induction of apoptosis in both BET inhibitor sensitive and resistant cells. Further we showed that combination of JQ1 with cisplatin led to significantly improved anti-tumor efficacy in A549 tumor-bearing mice. Altogether, these results show that the identification of BET-dependent genes provides guidance for the choice of drug combinations in cancer treatment. They also demonstrate that BET inhibition primes NSCLC cells for induction of apoptosis and that a combination with pro-apoptotic compounds represents a valuable strategy to overcome treatment resistance.
Highlights
In the last years, epigenetic regulators have become attractive targets for therapy of complex diseases like cancer, in which genetic and epigenetic alterations have essential roles
The combination of JQ1 and cisplatin further enhanced the effects of Bromodomain and extra terminal domain (BET) inhibition in JQ1-sensitive cells, while promoting apoptosis and reducing tumor growth in cells that showed a poor response to JQ1 alone
Our results were in agreement with recent findings describing the efficacy of BET inhibitors in a KRAS-driven non-small cell lung cancers (NSCLC) mouse model.[11]
Summary
Epigenetic regulators have become attractive targets for therapy of complex diseases like cancer, in which genetic and epigenetic alterations have essential roles. Resistance mechanisms by which a tumor evades drug-dependent cell death have been attributed to alterations in the apoptosis pathway.[22] One of the key anti-apoptotic regulators overexpressed in NSCLC is the cellular FLICE-like inhibitory protein (c-FLIP), which binds to pro-caspase 8 and thereby regulates its activation by FADD (Fas-associated death domain protein) bound death receptors such as Fas, DR4, DR5 and TNF-R1.23,24 In addition, cytoplasmic overexpression of c-FLIP has been linked to poor overall survival in NSCLC patients.[25] Because of the structural similarity with caspase 8, direct targeting of c-FLIP with small molecules is challenging. The combination of JQ1 and cisplatin further enhanced the effects of BET inhibition in JQ1-sensitive cells, while promoting apoptosis and reducing tumor growth in cells that showed a poor response to JQ1 alone
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