Mutations in the epidermal growth factor receptor gene (EGFR) are frequently 
observed in non-small-cell lung cancer (NSCLC), occurring in about 40% to 60% of 
never-smokers and in about 17% of patients with adenocarcinomas. EGFR tyrosine 
kinase inhibitors (TKIs), such as gefitinib and erlotinib, have transformed 
therapy for patients with EGFR-mutant NSCLC and have proved superior to 
chemotherapy as first-line treatment for this patient group. Despite these 
benefits, there are currently 2 key challenges associated with EGFR inhibitor 
therapy for patients with NSCLC. First, only 85% to 90% of patients with the 
EGFR mutation derive clinical benefit from EGFR TKIs, with the remainder 
demonstrating innate resistance to therapy. Second, acquired resistance to EGFR 
TKIs inevitably occurs in patients who initially respond to therapy, with a 
median duration of response of about 10 months. Mutant EGFR activates various 
subcellular signaling cascades, including the phosphatidylinositol 3-kinase 
(PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, which demonstrates 
maintained activity in a variety of TKI-resistant cancers. Given the fundamental 
role of the PI3K/Akt/mTOR pathway in tumor oncogenesis, proliferation, and 
survival, PI3K pathway inhibitors have emerged as a possible solution to the 
problem of EGFR TKI resistance. However resistance to EGFR TKIs is associated 
with considerable heterogeneity and complexity. Preclinical experiments 
investigating these phenomena suggest that in some patients, PI3K inhibitors 
will have to be paired with other targeted agents if they are to be effective. 
This review discusses the preclinical data supporting PI3K/Akt/mTOR pathway 
inhibitor combinations in EGFR TKI-resistant NSCLC from the perspective of the 
various agents currently being investigated in clinical trials.