Acute myeloid leukemia (AML): MDM2 inhibitors and BET inhibitors work synergistically to promote significant anti-leukemia activity


Scientists have identified two drugs that are potent against acute myeloid leukemia (AML) when combined, but only weakly effective when used alone.

The researchers were able to significantly enhance cancer cell death by jointly administering the drugs that are only partially effective when used as single-agent therapies. The study, a collaboration between Sanford Burnham Prebys Medical Discovery Institute and the University of Glasgow, was recently published in the journal Nature Communications.

“Our study shows that two types of drugs, MDM2 inhibitors and BET inhibitors, work synergistically to promote significant anti-leukemia activity,” says Peter Adams, Ph.D., a professor at Sanford Burnham Prebys and senior author of the study.

“The results were surprising because previous research had shown that each drug on its own had modest benefit against AML. The new research provides scientific rationale to advance clinical studies of the drug combination in patients with AML.”

There are many types of AML, and different cases have different chromosome changes, gene mutations and epigenetic modifications, making it difficult for researchers to find novel therapies that will work for a substantial proportion of patients.

Although much progress has been made toward finding effective treatments in recent years, the long-term overall survival has stagnated. According to the American Cancer Society, the five-year survival rate for adults with AML remains less than 30%.

Notably, TP53, the most frequently mutated gene in all human cancers, is found unaltered in about 90% of AML patients. Since the product of the TP53 gene, p53, acts to suppress tumors, scientists have sought drugs that reactivate or boost its anti-cancer powers in AML, which should provide a clinical benefit. However, such drugs on their own have been disappointing in AML.

“We were interested in combining MDM2 and BET inhibitors because each showed encouraging pre-clinical activity, but limited activity when given to patients as a single agent,” says Adams.

“Previous research had shown that MDM2 inhibitors activate p53, and BET inhibitors suppress genes associated with leukemias—but not p53.

“Our research unexpectedly showed that like MDM2 inhibitors, BET inhibitors activate p53, but through a different pathway. BET inhibitors mute the power of a protein called BRD4, which we found is a p53 suppressor in AML,” says Adams.

“Between the two drugs, you end up with a ‘double whammy’ effect that fully unleashes the anti-cancer activity of p53.

“Better therapies for AML are desperately needed,” adds Adams. “This study illustrates that targeting BRD4 as part of a combination therapy holds promise for patients diagnosed with this very dangerous disease.”

Despite numerous advances in the knowledge of the molecular landscape of Acute Myeloid Leukemia (AML), there remains an unmet need to improve clinical outcomes; 5-year survival rates in 2019 for adults diagnosed with AML remain below 30% (Watts and Nimer, 2018).

AML is a genetically and epigenetically heterogeneous disease, characterized by recurrent but diverse chromosomal structural changes and genetic mutations associated with functionally distinct sub-groups (Klco et al., 2013; Papaemmanuil et al., 2016).

In addition to disease heterogeneity between patients, marked sub-clonal heterogeneity has also been observed within individual AML patients (de Boer et al., 2018). To date these disease features have posed a significant obstacle to finding novel targeted agents with a broad therapeutic reach.

One key unifying feature of AML, that could potentially be exploited to benefit many patients, is that the majority of cases exhibit wild-type TP53 (Klco et al., 2013; Papaemmanuil et al., 2016). In AML with wild-type TP53, the p53 tumour suppressor protein is commonly held functionally inert through dysregulation of the ARF-MDM2/4 axis, culminating in inactivation of p53 by its negative regulators, MDM2 and MDM4 (Prokocimer et al., 2017).

Drugs and small molecules have been developed that can activate p53 in cells expressing the wild-type gene (Khoo et al., 2014), with the goal of unleashing p53’s potent tumor suppressive functions. Clinical grade MDM2 inhibitors (MDM2i) have been tested in the clinic, for example RG7112 in hematological and solid tumors, with some encouraging, but limited, responses (Andreeff et al., 2016; Khoo et al., 2014).

Nevertheless, in pre-clinical studies, MDM2i cooperated with “standard-of-care” therapies, daunorubicin and cytarabine, to eradicate AML (Maganti et al., 2018); and the BCL2 inhibitor (Venetoclax) and MDM2i (Idasanutlin/RG7388 [a clinical grade RG7112 derivative with improved potency, selectivity and bioavailability] (Ding et al., 2013)) are also synthetic lethal in AML (Pan et al., 2017).

Other combination strategies have also demonstrated the utility of targeting wild-type p53 in AML (Minzel et al., 2018). Consistent with these studies, Andreeff et al have proposed that use of MDM2i to activate p53 will likely realize more benefit in combination therapies (Andreeff et al., 2016).

Bromodomain-containing protein 4 (BRD4) is a member of the bromodomain and extraterminal (BET) family proteins, characterized by two N-terminal bromodomains and an extraterminal domain (Roe and Vakoc, 2016). BRD4 has been shown to play a role in the activation of genes involved in cell growth – most notably c-MYC – through binding to acetylated histones and transcription factors, to which BRD4 then recruits transcriptional regulators, such as positive transcription elongation factor b (P-TEFb) and Mediator complex (Roe and Vakoc, 2016).

Although c-MYC translocations or mutations are not common in AML, the activation of c-MYC by multiple up-stream leukemic genetic aberrations has been recognized as a key hub in driving leukemogenesis (Delgado and Leon, 2010). Pre-clinical data has demonstrated that inhibition of BRD4 has efficacy across a range of AML subtypes (Dawson et al., 2011; Filippakopoulos et al., 2010; Zuber et al., 2011). Indeed, BET inhibitors (BETi) have entered early phase clinical trials for AML.

However, despite promising pre-clinical activity, their efficacy in treating AML as single agents has been modest (Amorim et al., 2016; Berthon et al., 2016; Chaidos et al., 2015; Dombret and Gardin, 2016), and as such it is likely that, like MDM2i, their strength lies in rational combination therapies.

In sum, both MDM2i and BETi have been considered as therapies for AML, but on their own have shown limited clinical activity (Amorim et al., 2016; Andreeff et al., 2016; Berthon et al., 2016; Chaidos et al., 2015; Dombret and Gardin, 2016; Khoo et al., 2014).

Given that both drugs can, in principle, target a broad spectrum of AML molecular subtypes and the two drugs have distinct modes of action, we set out to test the hypothesis that the concomitant reactivation of p53 and inhibition of BET family proteins, using MDM2i and BETi, could synergise to kill AML cells.

Here we present data showing superior efficacy of the drug combination over the single agents in genetically heterogenous AML cell lines, primary AML samples, and two relevant mouse models. We present mechanistic data demonstrating how this efficacious drug combination co-operates to induce pro-apoptotic p53 target genes.

reference link :

More information: Anne-Louise Latif et al, BRD4-mediated repression of p53 is a target for combination therapy in AML, Nature Communications (2021). DOI: 10.1038/s41467-020-20378-8


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