TPX2 overexpression promotes sensitivity to dasatinib in breast cancer by activating YAP transcriptional signaling

Mol Oncol. 2024 Jun;18(6):1531-1551. doi: 10.1002/1878-0261.13602. Epub 2024 Feb 15.

Abstract

Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN-positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN-associated genes in an inducible manner. We find that the overexpression of targeting protein for Xklp2 (TPX2) enhances sensitivity to the proto-oncogene c-Src (SRC) inhibitor dasatinib due to activation of the Yes-associated protein 1 (YAP) pathway. Furthermore, using breast cancer data from The Cancer Genome Atlas (TCGA) and a cohort of cancer-derived patient samples, we find that both TPX2 overexpression and YAP activation are present in a significant percentage of cancer tumor samples and are associated with poor prognosis; therefore, they are putative biomarkers for selection for dasatinib therapy.

Keywords: Hippo‐YAP/TAZ; SFK kinases; TPX2; chromosomal instability; dasatinib; mitosis.

MeSH terms

  • Adaptor Proteins, Signal Transducing* / genetics
  • Adaptor Proteins, Signal Transducing* / metabolism
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • Breast Neoplasms* / pathology
  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Cell Line, Tumor
  • Dasatinib* / pharmacology
  • Drug Resistance, Neoplasm / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Microtubule-Associated Proteins* / genetics
  • Microtubule-Associated Proteins* / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Proto-Oncogene Mas*
  • Signal Transduction* / drug effects
  • Transcription Factors* / genetics
  • Transcription Factors* / metabolism
  • YAP-Signaling Proteins* / genetics
  • YAP-Signaling Proteins* / metabolism

Substances

  • Dasatinib
  • Proto-Oncogene Mas
  • MAS1 protein, human
  • YAP-Signaling Proteins
  • Transcription Factors
  • Adaptor Proteins, Signal Transducing
  • YAP1 protein, human
  • Cell Cycle Proteins
  • TPX2 protein, human
  • Microtubule-Associated Proteins
  • Nuclear Proteins
  • Phosphoproteins