Differentiating Benign from Malignant Thyroid Tumors by Kinase Activity Profiling and Dabrafenib BRAF V600E Targeting
by
, , and
Riet Hilhorst
1,
Adrienne van den Berg
1,
Piet Boender
1,
Tom van Wezel
2,
Tim Kievits
1,†,
Rik de Wijn
1,
Rob Ruijtenbeek
1,‡,
Willem E. Corver
2,* and
Hans Morreau
2 1
PamGene International BV, 5211 HH ‘s-Hertogenbosch, The Netherlands
2
Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
*
Author to whom correspondence should be addressed.
†
Current address: Precision Medicine Lab, 5349 AE Oss, The Netherlands.
‡
Current address: GenMab, 3584 CT Utrecht, The Netherlands.
Cancers 2023, 15(18), 4477; https://doi.org/10.3390/cancers15184477
Submission received: 22 May 2023
/
Revised: 28 August 2023
/
Accepted: 5 September 2023
/
Published: 8 September 2023
(This article belongs to the Special Issue Thyroid Cancer: Diagnosis, Prognosis and Treatment)
Simple Summary
Recurrent non-medullary thyroid cancer (NMTC) is difficult to treat and therapy options are limited. Of the available compounds, serine/threonine kinase (STK) inhibitors are currently widely used. However, this form of targeted therapy is not always effective and additional response-related biological information may improve both accuracy and efficacy. Using in-depth STK activity profiling, in this study, we aimed to determine whether benign and malignant thyroid tumors can be differentiated based on these profiles. In addition, we analyzed the impact of the BRAF V600E-specific inhibitor dabrafenib, as well as the generic RAF inhibitors sorafenib and regorafenib, in a subgroup of BRAF V600E and non-BRAF V600E papillary thyroid carcinomas. We demonstrate that STK activity profiling can differentiate benign from malignant thyroid tumors. Furthermore, the BRAF V600E-specific inhibitor dabrafenib can distinguish BRAF V600E from non-BRAF V600E papillary thyroid carcinomas. We conclude that STK activity profiling is beneficial when the goal is to differentiate benign from malignant thyroid tumors. In addition, this approach aids in the selection of likely effective (novel) kinase inhibitors for treatment of recurrent thyroid and other cancers.
Abstract
Differentiated non-medullary thyroid cancer (NMTC) can be effectively treated by surgery followed by radioactive iodide therapy. However, a small subset of patients shows recurrence due to a loss of iodide transport, a phenotype frequently associated with BRAF V600E mutations. In theory, this should enable the use of existing targeted therapies specifically designed for BRAF V600E mutations. However, in practice, generic or specific drugs aimed at molecular targets identified by next generation sequencing (NGS) are not always beneficial. Detailed kinase profiling may provide additional information to help improve therapy success rates. In this study, we therefore investigated whether serine/threonine kinase (STK) activity profiling can accurately classify benign thyroid lesions and NMTC. We also determined whether dabrafenib (BRAF V600E-specific inhibitor), as well as sorafenib and regorafenib (RAF inhibitors), can differentiate BRAF V600E from non-BRAF V600E thyroid tumors. Using 21 benign and 34 malignant frozen thyroid tumor samples, we analyzed serine/threonine kinase activity using PamChip®peptide microarrays. An STK kinase activity classifier successfully differentiated malignant (26/34; 76%) from benign tumors (16/21; 76%). Of the kinases analyzed, PKC (theta) and PKD1 in particular, showed differential activity in benign and malignant tumors, while oncocytic neoplasia or Graves’ disease contributed to erroneous classifications. Ex vivo BRAF V600E-specific dabrafenib kinase inhibition identified 6/92 analyzed peptides, capable of differentiating BRAF V600E-mutant from non-BRAF V600E papillary thyroid cancers (PTCs), an effect not seen with the generic inhibitors sorafenib and regorafenib. In conclusion, STK activity profiling differentiates benign from malignant thyroid tumors and generates unbiased hypotheses regarding differentially active kinases. This approach can serve as a model to select novel kinase inhibitors based on tissue analysis of recurrent thyroid and other cancers.
