Renal cell carcinoma (RCC) is a lethal disease, the incidence of which is increasing. Current targeted molecular strategies employing tyrosine kinase inhibitors (TKIs) have led to a significant gains in overall survival in certain cancer subtypes including RCC. Despite the therapeutic progress, however, complete and robust responses have been noted in only a few cases. Moreover, about a quarter of the RCC patients are primarily refractory to treatment with TKIs. Although TKIs have been combined with other therapeutic agents in an attempt to improve efficacy and overcome drug resistance, such treatments were often associated with significant toxicities. Thus, the new therapeutic approach for such cases is instantly needed.
Summary of the Invention
Researchers from Fox Chase Cancer Center have applied CRISPR/Cas9 based high- throughput loss-of -function screening to identify new genes involved in the resistance to sunitinib, one of the most commonly used TKIs given to RCC patients. This screen identified farnesyltransferase-dependent proteins regulating endosomal/lysosomal formation as important factors contributing to sunitinib resistance. Consequently, treatment with a clinically relevant FTase inhibitor (FTIs), lonafarnib, completely reinstates the sensitivity of RCC cells to sunitinib both in vitro and in vivo. In addition, combinatorial treatment with sunitnib and lonafarnib was well tolerated in vivo on animal models, highlighting the potential promise in the clinic. Therefore, since targeted therapies have often given disappointing results when used as single agents in solid tumors, the new approachoffered herein strongly supports the rationale for combined treatment of RCC with TKIs and FTIs.
Patent Status: A patent application has been filed.
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Inna Khartchenko, MS, MBA
Director, Technology Transfer and New Ventures