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Cell cycle/apoptosis molecule expression correlates with imatinib response in patients with advanced gastrointestinal

Salvatore Romeo1, Maria Debiec-Rychter, Martine Van Glabbeke

  • 1Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|June 11, 2009
PubMed
Abstract

Insights

Altered expression of cell cycle regulators like p53 and p16 is common in gastrointestinal stromal tumors (GISTs). These patterns impact patient survival and response to imatinib therapy, suggesting new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gastroenterology

Background:

  • Altered expression of cell cycle and apoptosis regulators is implicated in tumor progression and therapeutic resistance.
  • Understanding these alterations in gastrointestinal stromal tumors (GISTs) may reveal patient subgroups and therapeutic targets.

Purpose of the Study:

  • To investigate the expression patterns of key cell cycle/apoptosis regulators in GIST patients.
  • To correlate these expression patterns with clinicopathologic data, genetic mutations, and response to imatinib therapy.
  • To identify potential biomarkers for predicting GIST patient outcomes and novel therapeutic strategies.

Main Methods:

  • Immunohistochemical analysis of p53, p16, p21, CHK2, CCND1, BCL2, CDK4, and MDM2 in 353 GIST patients from a phase III trial.
  • TP53 mutation screening in cases with presumed nonfunctional p53.
  • Correlation of protein expression with clinicopathologic features, KIT/PDGFRA mutations, and imatinib dosage.

Main Results:

  • Frequent impaired expression of BCL2 (78%), CHK2 (53%), p53 (50%), and p16 (47%) was observed.
  • Tumor site and KIT/PDGFRA mutation status influenced the expression of several regulators.
  • High expression of CHK2 and p21 correlated with significantly better progression-free survival (PFS) on high-dose imatinib.
  • Impaired p53, p16, BCL2, and CHK2 expression were independently associated with PFS.

Conclusions:

  • Impaired expression of p53, p16, BCL2, and CHK2 is a frequent event in advanced GISTs.
  • Specific expression patterns are linked to tumor origin, genetic profile, and progression-free survival.
  • Maintaining cell cycle and apoptosis pathways is crucial for an optimal response to imatinib treatment in GIST patients.

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