ur DNA analysis: it is less invasive than tissue biopsies and results are quicker to obtain. In addition, cfDNA can provide us with the opportunity to detect the current or real time mutation status of a tumour and ultimately could lead to serial Nutlin-3 Cancer sampling to assess tumour progression or the development of resistant mutations. This study has demonstrated that cfDNA analysis could provide an opportunity for the detection of tumour specific mutations in patients with advanced melanoma, allowing for speedy access to novel agents and enrolment into clinical studies without waiting for tissue procurement. This technology provides patients who have no available tissue samples with the opportunity to be considered for a study without having to undergo further invasive procedures to obtain tissue samples.
The study has demonstrated that the detection of BRAF mutations in BMY 7378 21102-95-4 cfDNA is not significantly prognostic in advanced melanoma, and that, provided high LDH patients are excluded from the study population, entering patients by cfDNA analysis into a BRAFt selected trial will not enrich for a poor prognostic study population. Further studies on AZD6244 and other targeted agents will focus on improving the tissue/ cfDNA concordance rate and will aim to further validate cfDNA as a surrogate marker for tumour DNA mutations and as an inclusion criterion for clinical studies. ACKNOWLEDGEMENTS We thank all the study investigators and patients involved in study D1532C00003, and Dr Miriam Banner, from MediTech Media, who provided editing assistance funded by AstraZeneca.
This work was supported by educational grants from AstraZeneca and Cancer Research UK. Conflict of interest Gillian Ellison, Maria CM Orr, Karin R Kemsley, Gael McWalter, Laura Y Blockley, Simon P Deardon, Clive Morris, Mireille Cantarini and Andrew Hughes are AstraZeneca employees who hold AstraZeneca shares. All other authors declare no conflict of interest. Abstract Accumulating evidence suggests that cancer can be envisioned as a signaling disease, in which alterations in the cellular genome affect the expression and/or function of oncogenes and tumour suppressor genes. This ultimately disrupts the physiologic transmission of biochemical signals that normally regulate cell growth, differentiation and programmed cell death. From a clinical standpoint, signal transduction inhibition as a therapeutic strategy for human malignancies has recently achieved remarkable success.
However, as additional drugs move forward into the clinical arena, intrinsic and acquired resistance to targeted agents becomes an issue for their clinical utility. One way to overcome resistance to targeted agents is to identify genetic and epigenetic aberrations underlying sensitivity/resistance, thus enabling the selection of patients that will most likely benefit from a specific therapy. Since resistance often ensues as a result of the concomitant activation of multiple, often overlapping, signaling pathways, another possibility is to interfere with multiple, cross talking pathways involved in growth and survival control in a rational, mechanism based, fashion. These concepts may be usefully applied, among others, to agents that target two major signal transduction pathways: the one initiated by epidermal growth factor receptor signaling and the one converging on mitogen activated protein kinase activation. Here we review the molecular mechanisms of sensitivity/resistance to EGFR inhibitors, as well as the rationale