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.
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.
Authors: Keith C Bible; Vera J Suman; Julian R Molina; Robert C Smallridge; William J Maples; Michael E Menefee; Joseph Rubin; Kostandinos Sideras; John C Morris; Bryan McIver; Jill K Burton; Kevin P Webster; Carolyn Bieber; Anne M Traynor; Patrick J Flynn; Boon Cher Goh; Hui Tang; Susan Percy Ivy; Charles Erlichman Journal: Lancet Oncol Date: 2010-09-17 Impact factor: 41.316
Authors: Alicia Algeciras-Schimnich; Dragana Milosevic; Bryan McIver; Heather Flynn; Honey V Reddi; Norman L Eberhardt; Stefan K G Grebe Journal: Clin Chem Date: 2010-01-07 Impact factor: 8.327
Authors: Rebecca E Schweppe; Joshua P Klopper; Christopher Korch; Umarani Pugazhenthi; Miriam Benezra; Jeffrey A Knauf; James A Fagin; Laura A Marlow; John A Copland; Robert C Smallridge; Bryan R Haugen Journal: J Clin Endocrinol Metab Date: 2008-08-19 Impact factor: 5.958
Authors: Ayman Oweida; Andy Phan; Benjamin Vancourt; Tyler Robin; Mohammad K Hararah; Shilpa Bhatia; Dallin Milner; Shelby Lennon; Laura Pike; David Raben; Bryan Haugen; Nikita Pozdeyev; Rebecca Schweppe; Sana D Karam Journal: Thyroid Date: 2018-06 Impact factor: 6.568