Inhibiting Autophagy

Abstract

The common clear cell subtype of renal cell carcinoma is associated with hereditary or acquired loss of function of the von Hippel-Lindau tumor suppressor, a key component in oxygen sensing, perpetuating a stressed state. Autophagy is primarily a highly conserved, catabolic process by which stressed cells shuttle damaged or effete organelles and proteins into autophagosomes for sequestration and digestion after fusion with lysosomes. Autophagy is directed by autophagy-related genes and is divided into 4 discrete steps: initiation, nucleation, maturation, and degradation. During early tumorigenesis, apoptosis is enhanced and autophagy is suppressed, allowing accumulation of mutations and emergence of genomic instability. Late, an "autophagic switch" occurs, promoting survival and limiting apoptosis. Compounds such as chloroquine and hydroxychloroquine that prevent acidification of the lysosomal compartment are the sole clinically available inhibitors of autophagy. Currently, there are more than 30 trials examining combinations of hydroxychloroquine with anticancer agents. The intricate effects of autophagy on the immune response complicate manipulation of autophagy as part of the antitumor strategy. Further understanding of basic mechanisms of renal cell carcinoma pathogenesis and of autophagy will enable development of the next generation of pharmacologic modulators of autophagy.