Cellular adaptation to cancer therapy along a resistance continuum [scRNA-seq: PDX]
Advancements in precision oncology over the past decades have led to new therapeutic interventions, but the efficacy of such treatments is generally limited by an adaptive process that fosters drug resistance. In addition to genetic mutations, recent research has identified a role for non-genetic plasticity in transient drug tolerance and the acquisition of stable resistance. However, the dynamics of cell-state transitions that occur in the adaptation to cancer therapies remain unknown and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell-state transitions accompanied by a progressive increase in cell fitness, which we denote as the 'resistance continuum'. This cellular adaptation involves a stepwise assembly of gene expression programmes and epigenetically reinforced cell states underpinned by phenotypic plasticity, adaptation to stress and metabolic reprogramming. Our results support the notion that epithelial-to-mesenchymal transition or stemness programmes-often considered a proxy for phenotypic plasticity-enable adaptation, rather than a full resistance mechanism. Through systematic genetic perturbations, we identify the acquisition of metabolic dependencies, exposing vulnerabilities that can potentially be exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell-state transitions. Overall design: The data refers to two sets of experiments using a patient derived xenograft model of high-grade serous ovarian cancer to study the cancer cell response to PARP inhibitor (talazoparib). In one set of experiments, we aimed to generate PARPi resistant tumors over three serial passages. Vehicles (2 replicates) and tumors from the first (2 replicates and third rounds (3 samples with 2 replicates) of treatment were collected for scRNA-Seq analysis. In a first round, mice were treated with a standard dose (0.33 mg/kg), which initially caused remission and treatment was interrupted. After an off-treatment period, tumors relapsed and treatment was re-introduced. Tumors did not respond to therapy upon relapse, thus indicating resistance (R1). One of the replicates (R1*) was reimplanted for a second round (R2) of treatment and this was followed by a third round (R3), both under continuous therapy. Again, tumors did not respond to therapy in both passages. In another set of experiments, PARPi (talazoparib) response was evaluated by treatment cohorts of mice (2 replicates each) with 4 doses (D1: 0.13 mg/kg , D2 0.23 mg/kg, D3: 0.33 mg/kg, D4: 0.66 mg/kg), plus untreated vehicles (2 replicates).