Abstract
Although treatment options for cancer patients are increasing every year, the drug resistance problem remains very present. It is very difficult to find a drug that acts equally on tumours of the same histology as the individual's genetic characteristics often determine the response to treatment. Furthermore, tumours that initially respond to anti-tumour therapy are able to adapt and develop resistance to the drug, while others do not. In addition, this usually implies resistance development to agents to which the cells have not been exposed, a phenomenon called cross-resistance or multidrug resistance. Given this situation, it has been suggested that the most appropriate treatment would be able to act in parallel on multiple pathways constitutively altered in tumour cells. Pemetrexed is a multitargeted antifolate that exerts its activity against folate-dependent enzymes involved in de novo pyrimidine and purine synthesis. It is currently in use in combination with cisplatin against malignant pleural mesothelioma and non-squamous non-small cell lung cancer with favourable results. By real-time RT-PCR gene expression assays and restoration viability assays we demonstrated that Pemetrexed targets folate-dependent enzymes involved in de novo biosynthesis of purines differently depending on the intrinsic genetic characteristics of the tumour. These differences did not, however, interfere either with the initial response to the drug or with the activation of apoptotic pathways. In addition, these genetic fingerprints can differentiate two groups of tumours: those capable of developing resistance to antifolate, and not capable. These results may be useful to employ targets gene expression as resistance markers, a valuable tool for identifying patients likely to receive combination therapy to prevent the development of resistance.
Highlights
There is increasing awareness of the importance of genetic background in individual susceptibility to cancer treatments
Active Akt is able to regulate several molecules involved in cell survival, both directly and indirectly, through mammalian target of rapamycin which is responsible for controlling the cell cycle, apoptosis and growth via the regulation of several downstream proteins [4,5,6,7,8,9,10]
Pathway Restoration XTT cell viability assays revealed that MTA-induced growth inhibition was not completely blocked by the preformed purine Hx in all cell lines (Figure 2A), but inclusion of dTh in the culture medium in order to eliminate the effect on the primary target thymidylate synthase (TS), reversed the growth inhibitory effects
Summary
There is increasing awareness of the importance of genetic background in individual susceptibility to cancer treatments. The intrinsic characteristics of each tumour enable them to be sensitive or refractory to the agent employed This is the case of inherent drug resistance to some antifolates where alterations of the reduced folate carrier (RFC) role results in the impaired drug uptake. The treatments do not always manage to eradicate all malignant cells, enabling tumour cells to adapt their genetic characteristics in order to achieve a survival advantage [2,3]. Modifications involve the overexpression of target molecules, downregulation of proapoptotic factors, upregulation of prosurvival mediators, or deregulation of genes involved in the DNA damage detection and repair systems [1] This is the case for the regulation that p63 exerts on Akt, where Akt activity induces survival of cancer cells upon cisplatin exposure [3]. Active Akt is able to regulate several molecules involved in cell survival, both directly and indirectly, through mammalian target of rapamycin (mTOR) which is responsible for controlling the cell cycle, apoptosis and growth via the regulation of several downstream proteins [4,5,6,7,8,9,10]
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