Abstract
Sequential application of target drugs is standard procedure after renal cell carcinoma (RCC) patients develop resistance. To optimize the sequence, antitumour effects of the mTOR inhibitor RAD001 or the tyrosine kinase inhibitor (TKI) sorafenib on RCC cells with acquired resistance to the TKI sunitinib was evaluated. RCC cells were exposed to 1 μM sunitinib for 24 hrs (as control) and for 8 weeks (to induce resistance) and then switched to RAD001 (5 nM) or sorafenib (5 μM) for a further 8 weeks. Tumour cell growth, cell cycle progression, cell cycle regulating proteins and intracellular signalling were then investigated. Short-term application of sunitinib (24 hrs) induced cell growth blockade with accumulation in the G2/M phase. RCC cells became resistant to sunitinib after 8 weeks, demonstrated by accelerated cell growth along with enhanced cdk1, cdk2, loss of p27, activation of Akt, Rictor and Raptor. Switching to sorafenib only slightly reduced growth of the sunitinib resistant RCC cells and molecular analysis indicated distinct cross-resistance. In contrast, full response was achieved when the cancer cells were treated with RAD001. p19 and p27 strongly increased, phosphorylated Akt, Rictor and Raptor decreased and the tumour cells accumulated in G0/G1. It is concluded that an mTOR-inhibitor for second-line therapy could be the strategy of choice after first-line sunitinib failure.
Highlights
The development of targeted drugs has led to significant improvement in the prognosis of metastatic renal cell carcinoma (RCC)
To determine the optimum sunitinib and sorafenib dosage, all RCC cell lines were treated with different drug concentrations and cell growth was evaluated. 0.1 lM sunitinib did not exert a significant growth blocking effect, whereas 0.5, 1 and 5 lM did (Fig. 1, representative for Caki-1)
Signs of toxicity became apparent when tumour cells were exposed to 10 lM sunitinib
Summary
The development of targeted drugs has led to significant improvement in the prognosis of metastatic renal cell carcinoma (RCC). It has been argued that the tumour may adapt to chronic drug use and avoid drug mediated growth control To overcome this obstacle, sequential therapy is considered an innovative option providing maximal efficacy with a minimum risk of therapeutic failure. Sequential therapy is considered an innovative option providing maximal efficacy with a minimum risk of therapeutic failure Still, it remains unclear which compound is best applied after patients have become resistant to a TKI based regimen. It remains unclear which compound is best applied after patients have become resistant to a TKI based regimen This could be an alternative TKI, which may act on similar pathways as the firstline TKI, or an mTOR-inhibitor, which might alter intracellular signalling pathways different from the one targeted by the first-line TKI [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
