Predicting the outcome of chemotherapy for lung cancer

https://doi.org/10.1016/j.coph.2006.01.011Get rights and content

Lung cancer is a worldwide problem. At the time of diagnosis, 50% of patients have advanced incurable disease. Different chemotherapy combinations — with or without targeted therapies — yield similar results despite the continuous efforts of clinicians. However, molecular biological studies have already shed a great deal of light on the existence of multiple genetic aberrations that can be useful for customizing treatment. mRNA transcripts involved in DNA repair pathways, such as ERCC1 and BRCA1, confer selective resistance to cisplatin or taxanes, whereas thioredoxin confers a broad spectrum of chemoresistance. Polymorphisms in DNA repair genes and methylation of checkpoint genes in circulating serum DNA could become important predictive markers of survival in certain cisplatin-based regimens. Epidermal growth factor receptor tyrosine kinase mutations are the crux of targeted therapies, whereas epithelial–mesenchymal transitions and HER3 mRNA levels are promising ancillary markers for treatment with epidermal growth factor receptor tyrosine kinase inhibitors.

Introduction

Lung cancer is characterized by enhanced cellular proliferation, resistance to apoptosis and chemotherapeutic agents, aberrant activation of tyrosine kinase (TK)-dependent signaling pathways, and perturbations in other signaling pathways [1]. It is the leading cause of death from cancer in many countries, and its cure rate remains dismally low despite the continuing endeavors of clinicians (Box 1). Present treatment for advanced lung cancer is unsatisfactory, and nearly 90% of newly diagnosed patients will die within two years. Customizing chemotherapy and epidermal growth factor receptor (EGFR)-targeted therapy can substantially improve survival [2, 3].

The major molecular determinants of chemosensitivity are dealt with in this review. DNA repair genes, particularly the tumor mRNA transcript levels, can serve as differential modulators of cytotoxicity. Certain DNA repair gene polymorphisms can have subtle effects on survival to selected chemotherapy. Growing evidence indicates that cell-cycle checkpoint 14-3-3 expression could be a predictive marker of chemoresistance, whereas EGFR mutations surface as a unique marker of sensitivity to EGFR TK inhibitors, mainly in lung cancer of never-smokers. Finally, we describe novel components of sensitivity related to EGFR TK inhibitors, involving the phenomenon of epithelial–mesenchymal transition (EMT).

Section snippets

Lung cancer in never-smokers: a different disease

Molecular epidemiological studies have reported that lung cancer patients with the lowest DNA repair capacity, as measured by functional assays in cultured lymphocytes [4] or by increased leukocyte DNA adducts [5], are younger at diagnosis (<60 years) [4, 5], female [4], light- [4] or never-smokers [5], or have a family history of cancer [4] (Box 1). (Recently, susceptibility to lung cancer has also been associated with a germline T790M drug resistance mutation in EGFR) [6••].) Furthermore, the

DNA repair gene, thioredoxin and YB-1 mRNA levels

The cytotoxic effect of platinum-based anticancer drugs is attributed to the formation of bulky platinum-DNA adducts. Removal of these adducts from the genomic DNA is conducted primarily by the nucleotide excision repair (NER) system. Cisplatin resistance appears to be associated with the increased removal of cisplatin-DNA adducts. Similar to cancer cells, cisplatin-induced DNA adducts in Saccharomyces cerevisiae are processed by components of the NER, recombination repair (RR) and translesion

Polymorphisms in DNA repair genes

Impaired DNA repair capacity can favorably affect survival in cisplatin/gemcitabine-treated NSCLC patients. To investigate the association between survival and genetic polymorphisms in any of the following — X-ray repair cross-complementing group 1 (XRCC1) and XRCC3, xeroderma pigmentosum group D (XPD), ERCC1, ligase IV, RRM1, TP53, cyclooxygenase-2, interleukin-6, peroxisome proliferator-activated receptor-γ, EGF, methylene-tetra-hydrofolate reductase and methionine synthase [24••] — 135 stage

Epigenetic inactivation of cell-cycle checkpoint 14-3-3

For patients with a tumor load 100 g in size (3 × 1010 neoplastic cells), it is estimated that 3.3% of the tumor DNA is fed into the circulation daily [26]. Hypermethylation in the promoter regions of tumor suppressor genes was reported in the serum of NSCLC patients. A striking feature of 14-3-3 proteins is their ability to bind a multitude of functionally diverse signaling proteins. This plethora of interacting proteins allows 14-3-3 to play important roles in a wide range of regulatory

EGFR gene mutations

EGFR mutations are present in NSCLC, especially in adenocarcinoma, and are the hallmark of responsiveness to EGFR TK inhibitors (a recent review on this subject has been published in this journal [30]). Two mutations account for approximately 90% of EGFR mutations in lung adenocarcinomas. The most common type is a short in-frame deletion of 9, 12, 15, 18 or 24 nucleotides in exon 19. The second most common mutation is a point mutation (CTG to CGG) in exon 21 that results in substitution of

Epithelial mesenchymal transition and EGFR mutations

Intriguingly, an EMT phenotype [35] has been linked to resistance to erlotinib in NSCLC cell lines and xenografts [36••]. EMT is a process whereby epithelial cell layers lose polarity and cell–cell contact, and undergo a dramatic remodeling of the cytoskeleton. Concurrent with a loss of epithelial cell adhesion and cytoskeletal components, cells undergoing EMT acquire expression of mesenchymal components [35]. A main feature of EMT is the loss of E-cadherin expression. Several important genes

Outcome in patients with EGFR mutations treated with erlotinib or gefitinib

Cappuzzo et al. [48] also reported EGFR mutations in 17% of 89 Italian second-line gefitinib-treated NSCLC patients. Response rate was 54% in patients with EGFR mutations versus 5% in those without; time to progression was 9.9 versus 2.6 months (mean difference, 7.3 months); median survival was 20.8 versus 8.4 months (mean difference, 12.4 months). They also analyzed EGFR gene copy numbers by fluorescent in situ hybridisation in 102 patients; response rate was 36% for FISH-negative patients

Conclusions

A wealth of data from molecular biological studies is paving the way for novel models of treatment that warrant validation according to the REMARK guidelines [29]. Tumor ERCC1 and BRCA1 transcript levels could be helpful in tailoring chemotherapy, and TRX-1 and YB-1 transcripts could be important predictive markers. Polymorphisms in DNA repair genes and the methylation of checkpoint genes in circulating tumor serum DNA could be important surrogate predictive markers. Recent findings on EGFR

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This study was partially supported by the Spanish Ministry of Health grants provided through Red Tematica de Investigacion Cooperativa de Centros de Cancer (CO-010) and Red de Centros de Epidemiologia y Salud Publica (RCESP), and by funding from La Fundacio Badalona Contra el Cancer and from La Fundacion Carvajal. The authors thank Renée Grupp and Lourdes Franquet for assistance with the manuscript.

References (62)

  • R. Rosell et al.

    Treatment of non-small-cell lung cancer and pharmacogenomics: where we are and where we are going

    Curr Opin Oncol

    (2006)
  • Q. Wei et al.

    Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study

    J Natl Cancer Inst

    (2000)
  • M. Peluso et al.

    DNA adducts and lung cancer risk: a prospective study

    Cancer Res

    (2005)
  • D.W. Bell et al.

    Inherited susceptibility to lung cancer may be associated with the T790M drug resistance mutation in EGFR

    Nat Genet

    (2005)
  • L.T. Nordquist et al.

    Improved survival in never-smokers vs current smokers with primary adenocarcinoma of the lung

    Chest

    (2004)
  • R.S. Herbst et al.

    TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer

    J Clin Oncol

    (2005)
  • D.A. Eberhard et al.

    Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib

    J Clin Oncol

    (2005)
  • V. Beljanski et al.

    DNA damage-processing pathways involved in the eukaryotic cellular response to anticancer DNA cross-linking drugs

    Mol Pharmacol

    (2004)
  • M. Taron et al.

    BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer

    Hum Mol Genet

    (2004)
  • J.E. Quinn et al.

    BRCA1 functions as a differential modulator of chemotherapy-induced apoptosis

    Cancer Res

    (2003)
  • R. Rosell et al.

    Transcripts in pretreatment biopsies from a three-arm randomized trial in metastatic non-small-cell lung cancer

    Oncogene

    (2003)
  • R. Rosell et al.

    Ribonucleotide reductase messenger RNA expression and survival in gemcitabine/cisplatin-treated advanced non-small cell lung cancer patients

    Clin Cancer Res

    (2004)
  • J.D. Davidson et al.

    An increase in the expression of ribonucleotide reductase large subunit 1 is associated with gemcitabine resistance in non-small cell lung cancer cell lines

    Cancer Res

    (2004)
  • K. Yanagisawa et al.

    Proteomic patterns of tumour subsets in non-small-cell lung cancer

    Lancet

    (2003)
  • I. Csiki et al.

    Thioredoxin-1 modulates transcription of cyclooxygenase-2 via hypoxia-inducible factor-1{alpha} in non-small cell lung cancer

    Cancer Res

    (2006)
  • N.B. Arnold et al.

    Thioredoxin is downstream of Smad7 in a pathway that promotes growth and suppresses cisplatin-induced apoptosis in pancreatic cancer

    Cancer Res

    (2004)
  • Y. Oda et al.

    Nuclear expression of Y-box-binding protein-1 correlates with P-glycoprotein and topoisomerase II alpha expression, and with poor prognosis in synovial sarcoma

    J Pathol

    (2003)
  • K. Kohno et al.

    The pleiotropic functions of the Y-box-binding protein, YB-1

    Bioessays

    (2003)
  • R. de las Peñas et al.

    Polymorphisms in DNA repair genes modulate survival in cisplatin-plus-gemcitabine-treated non-small-cell lung cancer patients

    Ann Oncol

    (2006)
  • G. Matullo et al.

    XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects

    Carcinogenesis

    (2001)
  • F. Diehl et al.

    Detection and quantification of mutations in the plasma of patients with colorectal tumors

    Proc Natl Acad Sci USA

    (2005)
  • Cited by (72)

    • Pharmacogenomics in Lung Cancer

      2018, IASLC Thoracic Oncology
    • Synthetic tambjamine analogues induce mitochondrial swelling and lysosomal dysfunction leading to autophagy blockade and necrotic cell death in lung cancer

      2017, Biochemical Pharmacology
      Citation Excerpt :

      Early diagnosis and advances in first-line treatments are not entirely effective in reducing this high mortality since conventional treatments have limited success. Therefore, the identification of novel anticancer compounds focused on different mechanisms of action is eagerly needed [6,7]. Based on the specific altered pH of cancer cells, modulation of intracellular pH has recently been proposed as a new therapeutic strategy against cancer.

    View all citing articles on Scopus
    View full text