Investigation of cell signalings and therapeutic targets in PTPRK-RSPO3 fusion-positive colorectal cancer

PLoS One. 2022 Sep 21;17(9):e0274555. doi: 10.1371/journal.pone.0274555. eCollection 2022.

Abstract

Introduction: Colorectal cancer (CRC) is one of the most deadly and common diseases in the world, accounting for over 881,000 casualties in 2018. The PTPRK-RSPO3 (P:R) fusion is a structural variation in CRC and well known for its ability to activate WNT signaling and tumorigenesis. However, till now, therapeutic targets and actionable drugs are limited in this subtype of cancer.

Materials and method: The purpose of this study is to identify key genes and cancer-related pathways specific for P:R fusion-positive CRC. In addition, we also inferred the actionable drugs in bioinformatics analysis using the Cancer Genome Atlas (TCGA) data.

Results: 2,505 genes were altered in RNA expression specific for P:R fusion-positive CRC. By pathway analysis based on the altered genes, ten major cancer-related signaling pathways (Apoptosis, Direct p53, EGFR, ErbB, JAK-STAT, tyrosine kinases, Pathways in Cancer, SCF-KIT, VEGFR, and WNT-related Pathway) were significantly altered in P:R fusion-positive CRC. Among these pathways, the most altered cancer genes (ALK, ACSL3, AXIN, MYC, TP53, GNAQ, ACVR2A, and FAS) specific for P:R fusion and involved in multiple cancer pathways were considered to have a key role in P:R fusion-positive CRC. Based on the drug-target network analysis, crizotinib, alectinib, lorlatinib, brigatinib, ceritinib, erdafitinib, infigratinib and pemigatinib were selected as putative therapeutic candidates, since they were already used in routine clinical practice in other cancer types and target genes of the drugs were involved in multiple cancer-pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Axin Protein / metabolism
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Crizotinib
  • ErbB Receptors / metabolism
  • Humans
  • RNA
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / metabolism
  • Signal Transduction
  • Thrombospondins / metabolism
  • Tumor Suppressor Protein p53* / metabolism
  • Tyrosine

Substances

  • Axin Protein
  • RSPO3 protein, human
  • Thrombospondins
  • Tumor Suppressor Protein p53
  • Tyrosine
  • Crizotinib
  • RNA
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases
  • PTPRK protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2

Grants and funding

This study was supported by a VHS Medical Center Research Grant, Republic of Korea (VHSMC22057), grant no 18-2018-023 from the SNUBH Research Fund, and The National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. 2022R1C1C1012986). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.