Despite many significant advances in cancer therapies, resistance still remains a critical problem preventing durable responses and complete cures. While it is important to dissect the molecular mechanisms of therapy resistance, understanding how resistance evolves can unveil additional therapeutic opportunities. A key question is if resistance is pre-existing in a rare sub-fraction of cancer cell clones or obtained by some cancer cell clones only upon treatment. This knowledge could dictate which therapeutic strategy to pursue: specifically targeting the pre-existing relevant subfraction with a second drug in a combination treatment or targeting the relevant mechanism that allows adaptation to the primary treatment. To assess if a resistant clone was inherently resistant or adapted under treatment, the treatment-naive condition needs to be investigated. However, these clones can be particularly rare, and finding them in a complex cancer cell population is challenging. Classical sequencing approaches lack the necessary resolution, and conventional DNA barcoding experiments only allow indirect conclusions.
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