ANTI-TUMOUR TREATMENT
Markers involved in resistance to cytotoxics and targeted therapeutics in pancreatic cancer

https://doi.org/10.1016/j.ctrv.2008.10.002Get rights and content

Summary

Pancreatic cancer retains a poor prognosis among the gastrointestinal cancers and remains a challenge in oncology. In 1997, gemcitabine became the standard of care in metastatic setting. In the last decades, despite a number of clinical trials assessing novel cytotoxic agents and cell signaling inhibitors, overall survival has reached a plateau that remains difficult to improve. Development of mechanisms implicated in intrinsic and acquired resistance to chemotherapy are considered to play a key role that could explain the limited benefit of most treatment in pancreatic cancers. Key molecular factors implicated in this process include: deficiencies in drugs uptake, activations of DNA repair pathways, resistance to apoptosis, and tumor microenvironment. Moreover, for cell signaling inhibitors, mutations in kinase domains, activation of alternative pathways, mutations of genes downstream of the target, activation of autocrine/paracrine pathways and/or feed-back amplification of the target represent the most important mechanisms achieving resistance of pancreatic cancer cells.

Introduction

Pancreatic cancer retains a poor prognosis among the gastrointestinal cancer, with a 5-year overall survival (OS) of less than 5%. Recently, a large population-based study from the California Cancer Registry involving a total of 10,612 patients with pancreatic adenocarcinoma selected reported a median survival of 3.5 months for patients who had no surgical resection and of 13.3 months for those who underwent initial surgery.1 The poor survival associated with pancreatic cancer stems in part from the advanced stage at diagnosis for the majority of cases. Therefore, pancreatic adenocarcinoma still represents a therapeutic challenge in oncology.

Chemotherapy is the only treatment option in metastatic pancreatic cancer, and has been recently validated as the standard treatment in the adjuvant setting, as well as in locally advanced disease, in which situations (chemo)radiotherapy is no longer a standard treatment. Chemotherapeutic agents that are widely used in pancreatic cancer mainly include DNA-damaging agents, such as fluorouracil, oxaliplatin and gemcitabine. Ten years ago, Burris et al. showed in the palliative setting that gemcitabine was more effective than fluorouracil in improving disease-related symptoms and offered a slight but significant improvement in survival.2 Since then, many novel therapies were tested, including targeted therapies. Among them, only erlotinib that targets the epidermal growth factor receptor (EGFR) has been shown to improve survival used in combination with gemcitabine compared to gemcitabine alone.3 Nevertheless, it remains challenging to predict which patient will benefit from treatment and which one will suffer from drug toxicity. The clinical response rate to gemcitabine alone or in combination remains modest, mainly due to the intrinsic chemoresistance of pancreatic cancer cells. Investigating mechanisms mediating chemoresistance is therefore of clinical interest in drug development of new agents.4 In this paper, we aimed reviewing markers of resistance to cytotoxic agents and to molecular targeted therapies that may further help selecting patients who are more likely to benefit from these treatments and give a new direction for personalized treatment.

Section snippets

DNA-damaging agents

Our genome is vulnerable to an outfit of DNA-damaging agents, of both endogenous and environmental origin. Counteracting potentially cytotoxic and mutagenic accidents require constant excision and replacement of damaged nucleotide residues. Failures in DNA repair enzymes or in normal apoptosis pathways contribute to carcinogenesis by allowing accumulation of gene mutations, genetic instability and transgression of cell cycle checkpoints that would normally induce programmed cell death.

Perspectives

Despite technological advances, innovative treatments, and significant discoveries, treatment of pancreatic cancer remains a challenge. Chemotherapy is purely palliative with minimal impact on survival. Drug efficacy is limited because of many different unrelated mechanisms, including abnormal membrane receptor transport, inefficient metabolic drug conversion or increased metabolite inactivation, enhanced DNA repair and alterations in the apoptotic pathways. Moreover, the role of

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