Potential new therapy of Rapalink‐1, a new generation mammalian target of rapamycin inhibitor, against sunitinib‐resistant renal cell carcinoma

Abstract

This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. AbstractSunitinib, a multitargeted receptor tyrosine kinase inhibitor including vascular endothelial growth factor, has been widely used as a first-line treatment against metastatic renal cell carcinoma (mRCC). However, mRCC often acquires resistance to sunitinib, rendering it difficult to treat with this agent. Recently, Rapalink-1, a drug that links rapamycin and the mTOR kinase inhibitor MLN0128, has been developed with excellent therapeutic effects against breast cancer cells carrying mTOR resistance mutations. The aim of the present study was to evaluate the in vitro and in vivo therapeutic efficacy of Rapalink-1 against renal cell carcinoma (RCC) compared to temsirolimus, which is commonly used as a small molecule inhibitor of mTOR and is a derivative of rapamycin. In comparison with temsirolimus, Rapalink-1 showed significantly greater effects against proliferation, migration, invasion and cFolony formation in sunitinib-naïve RCC cells. Inhibition was achieved through suppression of the phosphorylation of substrates in the mTOR signal pathway, such as p70S6K, eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) and AKT. In addition, Rapalink-1 had greater tumor suppressive effects than temsirolimus against the sunitinib-resistant 786-o cell line (SU-R 786-o), which we had previously established, as well as 3 additional SU-R cell lines established here. RNA sequencing showed that Rapalink-1 suppressed not only the mTOR signaling pathway but also a part of the MAPK signaling pathway, the ErbB signaling pathway and ABC transporters that were associated with resistance to several drugs. Our study suggests the possibility of a new treatment option for patients with RCC that is either sunitinib-sensitive or sunitinib-resistant. K E Y W O R D SmTOR inhibitor, Rapalink-1, renal cell carcinoma, sunitinib resistance, temsirolimus

The Role of mTOR Signaling as a Therapeutic Target in Cancer

“…Rapalink-1 showed significantly greater effects against proliferation, migration, invasion, and colony formation in RCC cells. RNA sequencing showed that Rapalink-1 suppressed not only the mTOR signaling pathway but also a part of the MAPK signaling pathway, the ErbB signaling pathway, and ATP-binding cassette (ABC) transporters [ 178 ]. No large-sample clinical data have been reported for Rapalink.…”

Combining mTOR Inhibitors and T Cell-Based Immunotherapies in Cancer Treatment

“…In addition, RapaLink-1 targets glioblastoma stem cells and potentiates the anti-cancer efficacy of temozolomide, further supporting a therapeutic potential of RapaLink-1 in glioblastoma patients [ 52 ]. The anticancer benefit of RapaLink-1 is, however, not restricted to glioblastoma, as it also reduces the growth of sunitinib-resistant renal cell carcinoma tumor xenograft and prostate cancer patient-derived tumor xenograft [ 53 , 54 ].…”

Mechanistic Target of Rapamycin Inhibitors in Renal Cell Carcinoma: Potential, Limitations, and Perspectives

“…Two randomized phase 2 trials showed that the kinase inhibitor of mTOR AZD2014 (Powles et al, 2016b ) and the dual PI3K/mTOR inhibitor GDC-0980 (Powles et al, 2016a ) were inferior to everolimus in RCC patients who had progressed following exposure to VEGF pathway targeting therapies. Finally, a third-generation inhibitor named rapalink-1 and composed of rapamycin linked to the kinase inhibitor of mTOR MLN0128 provides improved anticancer efficacy in RCC models compared with temsirolimus (Kuroshima et al, 2020 ).…”