Therapeutic Targeting of Autophagy for Renal Cell Carcinoma Therapy

Abstract

Kidney cancer is the 7th most prevalent form of cancer in the United States with the vast majority of cases being classified as renal cell carcinoma (RCC). Multiple targeted therapies have been developed to treat RCC, but efficacy and resistance remain a challenge. In recent years, the modulation of autophagy has been shown to augment the cytotoxicity of approved RCC therapeutics and overcome drug resistance. Inhibition of autophagy blocks a key nutrient recycling process that cancer cells utilize for cell survival following periods of stress including chemotherapeutic treatment. Classic autophagy inhibitors such as chloroquine and hydroxychloroquine have been introduced into phase I/II clinical trials, while more experimental compounds are moving forward in preclinical development. Here we examine the current state and future directions of targeting autophagy to improve the efficacy of RCC therapeutics.

Keywords: ROC-325; autophagy; chloroquine; hydroxychloroquine; renal cell carcinoma.

Figure 1

Federal Drug Administration (FDA) approved agents to treat renal cell carcinoma (RCC). Various kinase and mammalian target of rapamycin (mTOR) inhibitors are amongst the most common drugs used, however, immune checkpoint inhibitors are becoming a mainstay of RCC treatment.

Figure 2

Selected agents that target autophagy at different points in the pathway. Hydroxychloroquine, chloroquine, and ROC-325 are amongst the compounds that target the lysosome. Compounds such as SBI-0206965 and SAR405 are being developed to inhibit autophagy factors near the proximal end of the cascade.