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Lung cancer is one of the main causes of cancer deaths in the world, and adenocarcinoma (ADC) subtype accounts for more than 50% of the cases. Cancer cells exhibit abilities for lipid uptake and can store them as lipid droplets (LDs). Lipids and lipid metabolism-related genes widely participate in the regulation of cancer cell viability, response and resistance to chemotherapy. In this study, we compared transcriptomic profiles from two lung ADC cell lines: i) H1299, containing LDs and expressing phospholipid transfer protein (PLTP), which facilitates the transfer of various lipid molecules; and ii) H1563 having no LDs and very low PLTP expression; and tested the responses of these cells to chemotherapeutic drugs- staurosporin, cisplatin and etoposide. According to the Annexin V-PE apoptosis detection assays, H1299 and H1563 cells revealed similar resistance to staurosporin (50 nM) but H1299 were more resistant (by 50%) to cisplatin (70 µM). The cell behavior was totally different in response to etoposide because a higher concentration (100µM) of this drug induced LDs formation in H1563, and these cells were more resistant (by 40%) to etoposide-induced apoptosis than H1299 cells. According to RNA-seq data, H1563 show higher expression of LPL (12-fold), FABP4 (9-fold) and CD36 (4-fold) than H1299 cells. Via LPL, cancer cells are able to acquire fatty acids (FA) from the circulation and CD36 facilitates cellular FA uptake. An anti-apoptotic and LPL-linked gene BCL2 (4-fold higher in H1563) may increase resistance to DNA-damage-inducing drugs, like etoposide. Hence, a better understanding of lipid role in carcinogenesis is crucial for advancements in diagnostic and treatment strategies in lung cancer.