Squamous cell lung carcinoma (SCC) accounts for 30% of patients with NSCLC and 
to date, no molecular targeted agents are approved for this type of tumor. 
However, recent studies have revealed several oncogenic mutations in SCC 
patients, including an alteration of the PI3K/AKT pathway, i.e. PI3K point 
mutations and amplification, AKT mutations and loss or reduced PTEN expression. 
Prompted by our observation of a correlation between PTEN loss and FAK 
phosphorylation in a cohort of patients with stage IV SCC, we evaluated the 
relevance of PTEN loss in cancer progression as well as the efficacy of a new 
combined treatment with the pan PI3K inhibitor buparlisip and the FAK inhibitor 
defactinib. An increase in AKT and FAK phosphorylation, associated with 
increased proliferation and invasiveness, paralleled by the acquisition of 
mesenchymal markers, and overexpression of the oncomir miR-21 were observed in 
SKMES-1-derived cell clones with a stable reduction of PTEN. Notably, the 
combined treatment induced a synergistic inhibition of cell proliferation, and a 
significant reduction in cell migration and invasion only in cells with reduced 
PTEN. The molecular mechanisms underlying these findings were unraveled using a 
specific RTK array that showed a reduction in phosphorylation of key kinases 
such as JNK, GSK-3 α/β, and AMPK-α2, due to the concomitant decrease in AKT and 
FAK activation. In conclusion, the combination of buparlisib and defactinib was 
effective against cells with reduced PTEN and warrants further studies as a 
novel therapeutic strategy for stage IV SCC patients with loss of PTEN 
expression.