Figure 3.

Schematic representation of the clinical response to targeted therapy in NSCLC patients. Primary resistance (red line) is characterised by a lack of initial response and a fast progression. Most patients display an initial response (blue line), with sometimes an apparently complete clearance of the tumour, although minimal residual disease persists and ultimately causes relapse in the vast majority of patients. Two hypotheses might explain the appearance of resistance for both primary and acquired resistance and might even co-exist within the same tumour. The Darwinian model suggests that, before the treatment, a population of sensitive cells (blue) co-exist with resistant cells (red) in treatment-naïve tumours, and pre-existing resistant cells are selected during treatment. The Lamarckian model suggests that a rare subpopulation of cells survives under treatment as the drug-tolerant persisters (DTPs). DTP cells exhibit non-genetic mechanisms of tolerance, slow-cycling capacities and a reversible phenotype, and could mimic the minimal residual disease phase observed in patients. DTP may eventually acquire drug-resistant mechanisms (green) and regain proliferative capacities. To study the minimal residual disease, several models are being used: most often cells treated with targeted therapies; xenograft models implanted in treated mice; and very rarely using biopsies from patients under treatment.