The MET inhibitor AZD6094 (Savolitinib, HMPL-504) induces regression in papillary renal cell carcinoma patient derived xenograft models
Menée à l'aide de deux xénogreffes dérivées de patients atteints d'un carcinome papillaire à cellules rénales, cette étude évalue l'acitvité antitumorale du savolitinib, un inhibiteur de MET
Purpose:Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with non-localized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occur in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and anti-tumor response of the selective MET inhibitor AZD6094 in two PRCC patient derived xenograft (PDX) models Experimental Design:Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and anti-tumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared to the activity of the RCC standard of care sunitinib (in RCC43b) or the multi-kinase inhibitor crizotinib (in RCC47) Results:AZD6094 treatment resulted in tumor regressions whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a dose and time dependent induction of cleaved PARP, a marker of cell death. Conclusions:Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication.