Our study findings not only established the relevance of autocrine TGFβ2 in early adaptive EGFR-TKI drug-escape in EGFR-mutant NSCLC, but also highlight for the first time, to our best knowledge, that TGFβ2 signaling links with the mitochondrial BCL-2/BCL-xL prosurvival cascade in the context of a profound cellular metabolome reprogramming. Here, BCL2L1 is linked to non-small cell lung carcinoma.