Abstract
Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive and lethal cancer types due to the late diagnosis, high metastatic potential, and drug resistance. The development of novel therapeutic strategies is urgently needed. KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) is the major driver mutation gene for PDAC tumorigenesis. In this study, we mined cancer genomics data and identified a common KRAS-driven gene signature in PDAC, which is related to cell–cell and cell–extracellular matrix (ECM) interactions. Higher expression of this gene signature was associated with poorer overall survival of PDAC patients. Connectivity Map (CMap) analysis and drug sensitivity profiling predicted that a clinically approved JAK2 (Janus kinase 2)-selective inhibitor, fedratinib (also known as TG-101348), could reverse the KRAS-driven gene signature and exhibit KRAS-dependent anticancer activity in PDAC cells. As an approved treatment for myelofibrosis, the pharmacological and toxicological profiles of fedratinib have been well characterized. It may be repurposed for treating KRAS-driven PDAC in the future.
Highlights
The occurrence of pancreatic cancer has significantly ascended throughout the past decade
To identify the common gene signature associated with pancreatic ductal adenocarcinoma (PDAC), five microarray data sets (Table 1) were obtained from the National Center for Biotechnology Information (NCBI)-Gene Expression Omnibus (GEO) database [21]
As shown in the Venn diagrams (Figure 1A), we identified 53 upregulated and 2 downregulated genes that were common in PDAC tissues when compared with the adjacent normal tissues (Figure 1A)
Summary
The occurrence of pancreatic cancer has significantly ascended throughout the past decade. At the end of 2019, the latter has been granted a fast track designation by the United States Food and Drug Administration (FDA) for treating metastatic non-small-cell lung carcinoma with the KRASG12C mutation [11] Another exciting drug is the first oral pan-KRAS inhibitor, BI-1701963, which has been in a phase I clinical trial alone or in combination with the MEK (mitogen-activated protein/extracellular signal-regulated kinase) inhibitor, trametinib, for KRAS-mutated solid tumors (NCT04111458; https://clinicaltrials.gov/). We mined bioinformatics resources and identified a common PDAC gene signature that was driven by KRAS, but not by TP53, mutation This gene signature was associated with the regulation of cell–cell and cell–extracellular matrix (ECM) interactions. The reversion of this gene signature by a clinically approved JAK2 (Janus kinase 2) inhibitor, fedratinib ( known as TG-101348), may provide therapeutic benefit for KRAS-mutated PDAC patients
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