Targeting autophagy: a novel anticancer strategy with therapeutic implications for imatinib resistance

Abstract

Autophagy is an ancient, intracellular degradative system which plays important roles in regulating protein homeostasis and which is essential for survival when cells are faced with metabolic stress. Increasing evidence suggests that autophagy also functions as a tumor suppressor mechanism that harnesses the growth and/or survival of cells as they transition towards a rapidly dividing malignant state. However, the impact of autophagy on cancer progression and on the efficacy of cancer therapeutics is controversial. In particular, although the induction of autophagy has been reported after treatment with a number of therapeutic agents, including imatinib, this response has variously been suggested to either impair or contribute to the effects of anticancer agents. More recent studies support the notion that autophagy compromises the efficacy of anticancer agents, where agents such as chloroquine (CQ) that impair autophagy augment the anticancer activity of histone deacetylase (HDAC) inhibitors and alkylating agents. Inhibition of autophagy is a particularly attractive strategy for the treatment of imatinib-refractory chronic myelogenous leukemia (CML) since a combination of CQ with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) compromises the survival of even BCR-ABL-T315I+ imatinib-resistant CML. Additional studies are clearly needed to establish the clinical utility of autophagy inhibitors and to identify patients most likely to benefit from this novel therapeutic approach.

Keywords: autophagy; chronic myelogenous leukemia; imatinib; resistance.

Figure 1

Targeting the autophagy pathway in CML. Imatinib-resistant BCR-ABL⁺ CML are sensitive to a therapeutic combination of SAHA, a FDA-approved HDAC inhibitor, and CQ, a FDA-approved anti-malarial agent (Carew et al 2007). Here the overall efficacy of SAHA is thought to be compromised by its induction of the autophagy pathway, which is initiated by the formation of double-membraned autophagosomes from vesicular structures coined the phagophore. Autophagosomes deliver their cargo, bulk cytosolic material and organelles, to the lysosome, which degrades the cargo to provide essential building blocks and energy to the CML cell. The lysosomotropic agent CQ compromises lysosomal functions and thus derails the autophagy pathway, augmenting the killing power of SAHA to overcome imatinib resistance provoked by mutations in BCR-ABL and/or p53 (Carew et al 2007). Abbreviations: CML, chronic myelogenous leukemia; CQ, chloroquine; HDAC, histone deacetylase; SAHA, suberoylanilide hydroxamic acid.