DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

SL and CF share senior authorship.

Significance of this study

What is already known on this subject?

• Dual-specificity tyrosine regulated kinase  1A (DYRK1A) has distinct functions in different tumours.

• DYRK1B is a survival factor in pancreatic tumours.

• DYRK1A positively regulates epidermal growth factor receptor (EGFR) accumulation in glioblastoma.

• Overexpression of c-MET is a common alteration in pancreatic ductal adenocarcinoma (PDAC).

What are the new findings?

• DYRK1A has a protumorigenic role in PDAC.

• DYRK1A stabilises c-MET by inhibiting it being targeted for degradation.

• Patient tumours with DYRK1A^high also showed high c-MET and EGFR expression levels. DYRK1A protein expression positively correlated with c-MET.

How might it impact on clinical practice in the foreseeable future?

• Pharmacological inhibition of DYRK1A could represent a promising therapy for c-MET^high and EGFR-positive PDAC tumours.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) represents over 90% of all pancreatic malignancies. Although PDAC is a relatively rare tumour, it is the fourth leading cause of cancer deaths worldwide, with a median survival of 6 months and a 5-year survival rate of 8%.¹ Recent estimates indicate that PDAC will become the second leading cause of cancer-related mortality by 2030.² This dismal outlook is in part due to late diagnosis, at which point more than 70% of patients present with advanced disease. Recently, gemcitabine plus nab paclitaxel and FOLFIRINOX chemotherapies have shown a modest improvement in survival of patients with advanced disease.^{3 4}

Pancreatic carcinogenesis is well defined as a multistage process accompanied by distinct morphological and histological changes, resulting from molecular alterations that are acquired during malignant transformation. Exome, whole-genome sequencing and copy-number variation analysis have revealed a complex mutational landscape.^{5 6} Recently, integrated genomic studies of PDAC samples identified 32 recurrently mutated genes that aggregate into 10 core molecular pathways.⁷

Protein kinases are key regulators of signal transduction pathways, and thereby their aberrant activation plays crucial roles in multiple cellular processes that lead to cancer progression.⁸ Indeed, protein kinases represent the most effective class of therapeutic targets in cancer.⁹ The dual-specificity tyrosine-regulated kinases (DYRKs) are a highly conserved family of protein kinases within the CMGC group of the eukaryote kinome. Based on phylogenetic analysis, the family is subdivided in two groups, known as class I and class...