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درمان هدفمند
Understanding, circumventing, and ultimately treating acquired resistance to targeted therapies will require monitoring for multiple molecular mechanisms; acquired drug resistance- associated mutations (such as the T790M-EGFR mutation in lung cancer or emergence of KRAS mutations in colorectal cancer; refs. 101-104) will be measured by either ctDNA or CTC analyses, whereas more complex mechanisms (including EMT or transversions from non-small cell to small cell histolo- gies; ref. 17) will require whole-cell analyses.
Using this approach, blood samples collected from a patient before and after drugresistant disease relapse could potentially be used to generate CDX models that could subsequently be characterized and compared in order to search for new druggable targets; routine in vivo testing of the cor responding targeted therapies would also be possible, thus facilitating the development of personalized medi cine strategies.
Beyond colorectal cancer, evidence of successful rechallenge strategies with targeted therapies can be found in patients with other tumour types, par ticularly melanoma or NSCLC159-163, but the molecular evolution has not been documented using liquid biopsy approaches.
Importantly, ctDNA analyses have been instrumen tal in demonstrating that responses to targeted therapies can be driven by distinct resistance mechanisms arising within separate tumour lesions in the same patient3,164.
Treatment with targeted therapies places tumour cells under selective pressure, thereby triggering clonal evolution that can be captured using liquid biopsy approaches.
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