Figure 6. Sequential temporally constrained delivery of a taxane and SFK inhibitor regresses tumour growth rate and overcomes adaptive resistance.
(a) Graph indicates tumour volume over time from heterotopic, syngeneic murine mammary carcinoma model (4T1). Groups were treated with docetaxel (DTX) or vehicle (black arrows show treatment days). Tumours were extracted on day 9 and 19 (Red arrows) corresponding to plateau or regrowth of tumour volume in docetaxel-treated arms, respectively (Data shown are mean±s.e.m., n=4). (b) Representative IHC of CD44 and pHCK following tumour extraction at indicated time points, H&E from serial sections confirm viable regions of tumour. Scale bar, 50 μm (c) Schematic shows experimental design for temporal delivery of dasatinib (10 mg kg−1) administered in two schedules, (1) 72 h or (2) 216 h post DTX treatment. The first schedule is designed to target the induction phase of chemotherapy-phenotypic transitioning and the second schedule targets the recalibration phase to parental state. (d) Histogram quantifies specific tumour growth rate. (e) Kaplan–Meier survival graph of an orthotopic syngeneic mammary carcinoma model treated as indicated (N=4 in all groups, N=3 for vehicle). (f) Representative confocal microscopy shows co-staining of CD44 and pHck. Regions of robust Hck activity correspond to regions of tumour with high expression of CD44 (areas outside yellow circumscription). Scale bar, 25 μm