Development and characterization of a differentiated thyroid cancer cell line resistant to VEGFR-targeted kinase
Crescent R Isham1, Brian C Netzel, Ayoko R Bossou
1Division of Medical Oncology (C.R.I., A.R.B., K.C.B.), Department of Oncology, and Department of Laboratory Medicine and Pathology (B.C.N., D.M., K.W.C., S.K.B.), and the Endocrine Malignancies Disease Oriented Group (C.R.I., A.R.B., S.K.G., K.C.B.), Mayo Clinic, Rochester, Minnesota 55905.
Background:
Vascular endothelial growth factor-targeted kinase inhibitors have emerged as highly promising therapies for radioiodine-refractory metastatic differentiated thyroid cancer. Unfortunately, drug resistance uniformly develops, limiting their therapeutic efficacies and thereby constituting a major clinical problem.
Approach And Methods:
To study acquired drug resistance and elucidate underlying mechanisms in this setting, BHP2-7 human differentiated thyroid cancer cells were subjected to prolonged continuous in vitro selection with 18 μM pazopanib, a clinically relevant concentration; acquisition of pazopanib resistance was serially assessed, with the resulting resistant cells thereafter subcloned and characterized to assess potential mechanisms of acquired pazopanib resistance.
Results:
Stable 2- to 4-fold in vitro pazopanib resistance emerged in response to pazopanib selection associated with similar in vitro growth characteristics but with markedly more aggressive in vivo xenograft growth. Selected cells were cross-resistant to sunitinib and to a lesser extent sorafenib but not to MAPK kinase (MEK1/2) inhibition by GSK1120212. Genotyping demonstrated acquisition of a novel activating KRAS codon 13 GGC to GTT (glycine to valine) mutation, consistent with the observed resistance to upstream vascular endothelial growth factor receptor inhibition yet sensitivity to downstream MAPK kinase (MEK1/2) inhibition.
Conclusions:
Selection of thyroid cancer cells with clinically utilized therapeutics can lead to acquired drug resistance and altered in vivo xenograft behavior that can recapitulate analogous drug resistance observed in patients. This approach has the potential to lead to insights into acquired treatment-related drug resistance in thyroid cancers that can be subjected to subsequent validation in serially collected patient samples and that has the potential to yield preemptive and responsive approaches to dealing with this important clinical problem.
Insights
Acquired resistance to vascular endothelial growth factor-targeted kinase inhibitors in thyroid cancer cells was studied. A KRAS mutation led to resistance, suggesting new therapeutic strategies for drug-resistant thyroid cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Vascular endothelial growth factor (VEGF)-targeted kinase inhibitors show promise for radioiodine-refractory metastatic differentiated thyroid cancer.
- Acquired drug resistance to these therapies is a significant clinical challenge, limiting treatment efficacy.
Purpose of the Study:
- To investigate the mechanisms of acquired drug resistance in differentiated thyroid cancer.
- To elucidate how prolonged exposure to pazopanib affects cancer cell behavior and genetic makeup.
Main Methods:
- BHP2-7 human differentiated thyroid cancer cells were selected in vitro with pazopanib.
- Resistant cells were subcloned and characterized for drug resistance profiles and genetic alterations.
- In vivo xenograft growth was assessed to evaluate tumor aggressiveness.
Main Results:
- Stable 2- to 4-fold pazopanib resistance developed, with increased in vivo xenograft growth.
- Cross-resistance to sunitinib and sorafenib was observed, but not to MEK1/2 inhibition.
- A novel activating KRAS codon 13 mutation was identified in resistant cells.
Conclusions:
- In vitro selection can model acquired drug resistance seen in patients with thyroid cancer.
- The KRAS mutation explains resistance to VEGF inhibitors and sensitivity to MEK inhibitors.
- This model provides insights for developing preemptive strategies against drug resistance in thyroid cancer.
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