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Published on: January 7, 2019
Molecular subtype and response to dasatinib, an Src/Abl small molecule kinase inhibitor, in hepatocellular carcinoma
Richard S Finn1, Alexey Aleshin, Judy Dering
1Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Rfinn@mednet.ucla.edu
Unlabelled:
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and is the third leading cause of cancer death worldwide. Recently, the multitargeted kinase inhibitor sorafenib was shown to be the first systemic agent to improve survival in advanced HCC. Unlike other malignancies such as breast cancer, in which molecular subtypes have been clearly defined (i.e., luminal, HER2 amplified, basal, etc.) and tied to effective molecular therapeutics (hormone blockade and trastuzumab, respectively), in HCC this translational link does not exist. Molecular profiling studies of human HCC have identified unique molecular subtypes of the disease. We hypothesized that a panel of human HCC cell lines would maintain molecular characteristics of the clinical disease and could then be used as a model for novel therapeutics. Twenty human HCC cell lines were collected and RNA was analyzed using the Agilent microarray platform. Profiles from the cell lines in vitro recapitulate previously described subgroups from clinical material. Next, we evaluated whether molecular subgroup would have predictive value for response to the Src/Abl inhibitor dasatinib. The results demonstrate that sensitivity to dasatinib was associated with a progenitor subtype. Dasatinib was effective at inducing cell cycle arrest and apoptosis in "progenitor-like" cell lines but not in resistant lines.
Conclusion:
These findings suggest that cell line models maintain the molecular background of HCC and that subtype may be important for selecting patients for response to novel therapies. In addition, it highlights a potential role for Src family signaling in this progenitor subtype of HCC.
Insights
Hepatocellular carcinoma (HCC) cell lines mirror clinical subtypes, showing that progenitor-like HCC may respond to dasatinib, a targeted therapy. This highlights the potential of molecular subtypes for guiding HCC treatment decisions.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer death globally.
- Current treatments for advanced HCC, like sorafenib, offer limited survival benefits.
- Unlike other cancers, HCC lacks defined molecular subtypes linked to targeted therapies.
Purpose of the Study:
- To establish and validate human HCC cell lines as models for studying molecular subtypes.
- To investigate if molecular subtypes predict response to targeted therapies in HCC.
Main Methods:
- Collected and analyzed RNA from twenty human HCC cell lines using microarray.
- Compared cell line molecular profiles to previously identified clinical HCC subgroups.
- Assessed sensitivity of HCC cell lines to the Src/Abl inhibitor dasatinib based on molecular subtype.
Main Results:
- HCC cell line molecular profiles recapitulated known clinical HCC subgroups.
- Sensitivity to dasatinib was significantly associated with a progenitor molecular subtype.
- Dasatinib induced cell cycle arrest and apoptosis in progenitor-like HCC cell lines, but not in resistant lines.
Conclusions:
- Human HCC cell line models accurately reflect the molecular heterogeneity of clinical HCC.
- Molecular subtyping may be crucial for predicting patient response to novel HCC therapies.
- Src family signaling is implicated in the progenitor subtype of HCC, suggesting a therapeutic target.
