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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Pharmacologic screen identifies active combinations with BET inhibitors and LRRK2 as a novel putative target in
Filippo Spriano1, Giulio Sartori1, Chiara Tarantelli1
1Institute of Oncology Research Faculty of Biomedical Sciences Università della Svizzera Italiana Bellinzona Switzerland.
Abstract:
Inhibitors of the Bromo- and Extra-Terminal domain (BET) family proteins have strong preclinical antitumor activity in multiple tumor models, including lymphomas. Limited single-agent activity has been reported in the clinical setting. Here, we have performed a pharmacological screening to identify compounds that can increase the antitumor activity of BET inhibitors in lymphomas. The germinal center B-cell like diffuse large B-cell lymphoma (DLBCL) cell lines OCI-LY-19 and WSU-DLCL2 were exposed to 348 compounds given as single agents at two different concentrations and in combination with the BET inhibitor birabresib. The combination partners included small molecules targeting important biologic pathways such as PI3K/AKT/MAPK signaling and apoptosis, approved anticancer agents, kinase inhibitors, epigenetic compounds. The screening identified a series of compounds leading to a stronger antiproliferative activity when given in combination than as single agents: the histone deacetylase (HDAC) inhibitors panobinostat and dacinostat, the mTOR (mechanistic target of rapamycin) inhibitor everolimus, the ABL/SRC (ABL proto-oncogene/SRC proto oncogene) inhibitor dasatinib, the AKT1/2/3 inhibitor MK-2206, the JAK2 inhibitor TG101209. The novel finding was the benefit given by the addition of the LRRK2 inhibitor LRRK2-IN-1, which was validated in vitro and in vivo. Genetic silencing demonstrated that LRRK2 sustains the proliferation of lymphoma cells, a finding paired with the association between high expression levels and inferior outcome in DLBCL patients. We identified combinations that can improve the response to BET inhibitors in lymphomas, and LRRK2 as a gene essential for lymphomas and as putative novel target for this type of tumors.
Insights
This study identified compounds that enhance the antitumor effects of Bromo- and Extra-Terminal domain (BET) inhibitors in lymphoma. The leucine-rich repeat kinase 2 (LRRK2) inhibitor LRRK2-IN-1 showed significant promise, with LRRK2 identified as a crucial gene in lymphoma proliferation.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Bromo- and Extra-Terminal domain (BET) protein inhibitors show preclinical antitumor activity in lymphomas but limited clinical efficacy as single agents.
- Identifying combination therapies is crucial to enhance the therapeutic potential of BET inhibitors in treating lymphomas.
Purpose of the Study:
- To conduct a pharmacological screen to discover compounds that potentiate the antitumor activity of BET inhibitors in lymphoma models.
- To identify novel therapeutic targets and combinations for lymphoma treatment.
Main Methods:
- A library of 348 compounds was screened for synergistic effects with the BET inhibitor birabresib in germinal center B-cell like diffuse large B-cell lymphoma (DLBCL) cell lines.
- Compounds were tested as single agents and in combination, targeting pathways including PI3K/AKT/MAPK, apoptosis, and epigenetic modifications.
- In vitro and in vivo validation of promising candidates, including genetic silencing and patient data analysis.
Main Results:
- Several compounds, including histone deacetylase (HDAC) inhibitors (panobinostat, dacinostat), mTOR inhibitor (everolimus), and kinase inhibitors (dasatinib, MK-2206, TG101209), enhanced antiproliferative activity in combination with birabresib.
- A novel finding was the significant benefit of the leucine-rich repeat kinase 2 (LRRK2) inhibitor LRRK2-IN-1, validated both in vitro and in vivo.
- Genetic silencing confirmed LRRK2's role in sustaining lymphoma cell proliferation, and high LRRK2 expression correlated with poorer outcomes in DLBCL patients.
Conclusions:
- Combinations of BET inhibitors with specific agents like HDAC inhibitors, mTOR inhibitors, and kinase inhibitors can improve response rates in lymphomas.
- LRRK2 is identified as an essential gene for lymphoma proliferation and a potential novel therapeutic target for these cancers.
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