DNA Repair and Mitotic Checkpoint Genes as Potential Predictors of Chemotherapy Response in Non-Small-Cell Lung Cancer

  • Rafael Rosell
  • Miquel Taron
  • Mariacarmela Santarpia
  • Fernanda Salazar
  • Jose Luis Ramirez
  • Miguel Angel Molina
Part of the Cancer Drug Discovery and Development™ book series (CDD&D)

Summary

Metastatic stage IV non-small-cell lung cancer (NSCLC) has a grim outcome. The median survival does not exceed 11 months, with no differences according to different cisplatin-based regimens. However, this clinical observation is spurious from the molecular point of view, bewcausse DNA repair genes involved in several pathways act as differential modulators of chemosensitivity. Low expression of ERCC1 or BRCA1 predicts higher sensitivity to cisplatin and other DNA-damaging agents, such as etoposide and mitomycin, while conferring resistance to antimicrotubule drugs, such as vinblastine and paclitaxel. In contrast, high expression of these genes confers resistance to cisplatin and sensitivity to antimicrotubules.

Although this principle has yet to be demonstrated in clinical studies, it can be postulated that patients with low expression of nucleotide excision repair (NER) or NER-related genes may be good candidates for cisplatin plus either gemcitabine, etoposide, or mitomycin plus ifosfamide for optimal survival. On the same grounds, patients whose tumors have relatively high expression of these genes can still benefit from cisplatin combined with antimicrotubule drugs.

The same premises of customization can be applied to early NSCLC. Various clinical observations indicate that when these defense NER genes are overexpressed in resected NSCLCs, they reflect a lower risk of relapse and increased cisplatin resistance. Several layers of evidence show that BRCA1 can be the most important predictive marker for customizing chemotherapy. In addition, the clinical value of several mitotic checkpoint genes that are dysfunctional in NSCLC and regulated by BRCA1 should also be investigated.

Key Words

Non-small-cell lung cancer DNA repair ERCC1 BRCA1 Mad2 BubR1 MZF1 mitotic checkpoint 

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Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Rafael Rosell
    • 1
  • Miquel Taron
    • 1
  • Mariacarmela Santarpia
    • 2
  • Fernanda Salazar
    • 1
  • Jose Luis Ramirez
    • 1
  • Miguel Angel Molina
    • 1
  1. 1.Catalan Institute of Oncology Hospital Germans Trias i Pujol Badalona(Barcelona)Spain
  2. 2.University of MessinaMessinaItaly

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