Electronic Cigarettes Increase Blood-Brain and Blood-Tumor Barrier Drug Efflux in a Preclinical Lung Cancer Model of Brain Metastasis
Abstract
This dissertation (a) provided a comprehensive review of the known therapeutic challenges in nicotine delivery system users with lung cancer and (b) investigated the impact of electronic cigarettes on blood-brain/blood-tumor barrier function and efficacy of small molecule KRAS inhibitors in a syngeneic lung cancer brain metastasis model. The blood-brain barrier is a physiochemical barrier that limits systemic delivery of therapeutics into brain. When tumors invade the central nervous system, the blood-brain barrier is disrupted and subsequently forms a blood-tumor barrier. Despite the inherent leakiness and variable permeability of the blood-tumor barrier, it continues to restrict anti-cancer drugs from accumulating at therapeutic concentrations. Electronic cigarettes are shown to negatively impact blood-brain barrier function. Whether this results in changes in drug delivery and/or progression of brain metastases remains unknown. This is of importance due to the effects of smoking on lung cancer progression and increasing popularity of electronic cigarette use in smoking-related cancers. Our findings show that although electronic cigarettes do not disrupt the integrity of the blood-brain barrier, exposure increases the activity of efflux transporters. This results in reduced efficacy of adagrasib, a recently approved KRAS inhibitor that is subject to efflux at the blood-brain barrier. This work emphasizes the physiological impacts of electronic cigarettes on progression of…
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