The Influence of Metabolism on Drug Response in Cancer

Abstract

Resistance to therapeutic agents, either intrinsic or acquired, is currently a major problem in the treatment of cancers and occurs in virtually every type of anti-cancer therapy. Therefore, understanding how resistance can be prevented, targeted and predicted becomes increasingly important to improve cancer therapy. In the last decade, it has become apparent that alterations in cellular metabolism are a hallmark of cancer cells and that a rewired metabolism is essential for rapid tumor growth and proliferation. Recently, metabolic alterations have been shown to play a role in the sensitivity of cancer cells to widely-used first-line chemotherapeutics. This suggests that metabolic pathways are important mediators of resistance toward anticancer agents. In this review, we highlight the metabolic alterations associated with resistance toward different anticancer agents and discuss how metabolism may be exploited to overcome drug resistance to classical chemotherapy.

A metabolic switch in proteasome inhibitor-resistant multiple myeloma ensures higher mitochondrial metabolism, protein folding and sphingomyelin synthesis

“…We suggest targeting the downstream pathways of high energy supply driven by mitochondria in PI-resistant cells, such as more effective protein folding or lipid homeostasis, as a promising strategy to selectively target the adaptive features of these PI-resistant MM cells. Our data support previous reports about high energy demand in PI-resistant cells 16 and highlight global metabolic mitochondrial changes leading to increased protein folding and lipid rewiring as major drivers of adaptation towards PI, and at the same time identify vulnerable spots in cellular homeostasis specifically in PI-resistant MM. The key findings are summarized in the hierarchical model for the metabolic adaptation of PI-resistant MM (Online…”

Complex Mitochondrial Dysfunction Induced by TPP+-Gentisic Acid and Mitochondrial Translation Inhibition by Doxycycline Evokes Synergistic Lethality in Breast Cancer Cells

“…This phenomenon determines the effect of several anticancer small molecules that have therapeutic targets related to OXPHOS [9,10]. Moreover, the metabolic heterogeneity of different subpopulations of cancer cells in the same tumor contributes to partial eradication/inhibition of tumor growth [11,12] and acquisition of resistance to chemotherapeutics [13,14]. Therefore, elucidation of the induction of the metabolism-dependent adaptive responses of cancer cells may be exploited to identify new targets to produce tumor vulnerability and overcome drug resistance to classical chemotherapeutics.…”

GLUL Ablation Can Confer Drug Resistance to Cancer Cells via a Malate-Aspartate Shuttle-Mediated Mechanism

“…While deregulated cellular metabolism appears to be an emerging hallmark of cancer drug resistance [12][13][14][15], deregulated energetics involving alterations in cellular metabolism to support neoplastic proliferation is a fundamental hallmark of cancer [16]. Central to this metabolic deregulation is Warburg's discovery of aerobic glycolysis, where glucose is converted to lactate even when oxygen supply is sufficient to support oxidative phosphorylation.…”