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.
Highlights
It is estimated that over 73,000 new cases of renal cancer will be diagnosed in the United States this year, with upwards of 14,000 individuals succumbing to their disease [1]
Activated Mammalian target of rapamycin complex 1 (mTORC1) is responsible for adding an inhibitory phosphate at Serine 757 to the Unc-51-like kinase (ULK1) complex, which prevents the initiation of autophagy [30]
We have shown that ROC-325 does not affect the formation of autophagosomes but rather accumulates in and deacidifies the lysosome
Summary
It is estimated that over 73,000 new cases of renal cancer will be diagnosed in the United States this year, with upwards of 14,000 individuals succumbing to their disease [1]. Patients often undergo treatment with chemotherapy or immunotherapy depending on their histologic subtype. Targeted tyrosine kinase and mTOR inhibitors are effective first-line treatment options, many, if not all, cases of RCC will eventually become resistant to these drugs. A better understanding of the mechanistic drivers of drug resistance in RCC will facilitate the development of new and more effective treatment options for the relapsed/refractory patient population. A of protein 4 (CTLA-4) and programmed cell death ligand 1 (PD-L1) When these surface proteinsfew come these responsive genes code for vascular endothelial growth factor (VEGF), platelet-derived growth in contact with the appropriate receptor on T-cells, they effectively trick the lymphocyte into factor. PD-L1genes and CTLA-4 the immune cellsof torapamycin recognize the tumorpathway cells as aare foreign entity These cases [8,9].
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