Cancer cell metabolic plasticity allows resistance to NAMPT inhibition but invariably induces dependence on LDHA.

ABSTRACT:

Background

Inhibitors of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in NAD⁺ biosynthesis from nicotinamide, exhibit anticancer effects in preclinical models. However, continuous exposure to NAMPT inhibitors, such as FK866, can induce acquired resistance.

Methods

We developed FK866-resistant CCRF-CEM (T cell acute lymphoblastic leukemia) and MDA MB231 (breast cancer) models, and by exploiting an integrated approach based on genetic, biochemical, and genome wide analyses, we annotated the drug resistance mechanisms.

Results

Acquired resistance to FK866 was independent of NAMPT mutations but rather was based on a shift towards a glycolytic metabolism and on lactate dehydrogenase A (LDHA) activity. In addition, resistant CCRF-CEM c

SUBMITTER: Thongon N 

PROVIDER: S-EPMC5844108 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature