In this manuscript, we provide complementary biochemical and biological evidence that aberrant signalling through the PI3K/Akt pathway, due to gain-of-function mutation in Akt1 (E17K) or PIK3CA (E545K) or to PTEN loss, regulates self-renewal of NSCLC TICs in vitro and tumor growth in vivo by activating the NF-kB/IL-6/STAT3 axis. Here, STAT3 is linked to neoplasm.