Cutaneous squamous cell carcinoma (cSCC) is a common skin cancer. Most patients who develop metastases (2-5%) present with advanced disease that requires a combination of radical surgery and adjuvant radiation therapy. There are few effective therapies for refractory disease due in part to a lack of research integrating key molecular mechanisms with therapeutic response. The role of PI3K/AKT/mTOR signalling in cSCC has been gaining traction, with our own research identifying its significance in metastatic cSCC especially, suggesting a candidate target for therapeutics. To this end, we have utilised patient-derived cell lines of metastatic cSCC to investigate sensitivity towards PI3K/mTOR and FAK-signalling inhibitors. The PI3K/mTOR inhibitors PIK-75 and Dactolisib were found to effect cell viability at low nanomolar concentrations for both cell lines with sensitivity corresponding to copy number alterations. The focal adhesion kinase (FAK) inhibitor Y15 demonstrated a low micromolar potency against the cell lines accompanied with a reduction in cell adhesion and morphology in a time- and dose-dependent manner. High-dose Y15 quickly induced cell detachment leading to cell death. Changes in the actin-cytoskeleton induced by Y15 were investigated further through confocal microscopy, revealing the formation of stress fibres. Furthermore, a reduction of cell motility consecutive to Y15 treatment was observed. Both observation point towards a potential involvement of two GTPases, Rac and RhoA, regulating cell motility and stress fibre formation, respectively. PIK-75 and Dactolisib treatment decreased phosphorylated AKT whilst Y15 caused an increase. These data provide a link between molecular observations of PI3K/AKT/mTOR and FAK signalling and therapeutic response. Such compounds may prove useful where conventional treatments or biologics fall short in this disease.