Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance.

Abstract

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.

• Authors: Husain Yar Khan, James Ge, Misako Nagasaka, Amro Aboukameel, Gabriel Mpilla, Irfana Muqbil, Mark Szlaczky, Mahmoud Chaker, Erkan Baloglu, Yosef Landesman, Ramzi M Mohammad, Asfar S Azmi, Ammar Sukari
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 1 (Dec 29 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31905765 (Publication Type: Journal Article)

Chemical References

• ARHGAP21 protein, human
• Antineoplastic Agents
• GTPase-Activating Proteins
• Karyopherins
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Quinolines
• Receptors, Cytoplasmic and Nuclear
• PAK4 protein, human
• p21-Activated Kinases
• lenvatinib

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Drug Therapy, Combination
• GTPase-Activating Proteins (metabolism)
• Humans
• Karyopherins (antagonists & inhibitors, metabolism)
• Mice, Inbred ICR
• Mice, SCID
• Phenylurea Compounds (pharmacology, therapeutic use)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Quinolines (pharmacology, therapeutic use)
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Thyroid Carcinoma, Anaplastic (drug therapy, metabolism)
• Thyroid Neoplasms (drug therapy, metabolism)
• Transcriptome (drug effects, genetics)
• Xenograft Model Antitumor Assays
• p21-Activated Kinases (antagonists & inhibitors, metabolism)
• Exportin 1 Protein