克服肾细胞癌的先天性和适应性耐药性：联合使用新一代法尼基转移酶抑制剂KO-2806作为增强VEGF TKI疗效的策略.pdf

1、Overcoming Innate and Adaptive Resistance in RCCCombination of the Next-Generation Farnesyl Transferase Inhibitor,KO-2806,with a VEGF Receptor Tyrosine Kinase InhibitorJabed Seraj,MD Kura Oncology,Inc.SLIDE DIMENSIONS SHOULD FOLLOW 16:9 RATIOCurrent treatments for advanced renal cell carcinoma(RCC)i

2、nclude tyrosine kinase inhibitors(TKI)that target angiogenesis.The VEGF receptor TKI cabozantinib is an approved therapy in advanced RCC.Persistent mTORC1 activity is a frequent and consistent non-genetic driver of inherent and adaptive resistance to multiple classes of targeted therapies.KO-2806 is

3、 a next-generation farnesyl transferase inhibitor(FTI)that blocks hyperactivated growth factor signaling via mTORC1 by inhibiting farnesylation of RHEB while sparing mTORC2 inhibition and its associated toxicities.Rationale for use of a farnesyl transferase Rationale for use of a farnesyl transferas

4、e inhibitorinhibitor as a combination partner in RCCas a combination partner in RCCKOKO-2806 potentiates the anti2806 potentiates the anti-tumor activity of tumor activity of cabozantinibcabozantinib in TKIin TKI-nave RCC modelsnave RCC models Increased depth of response seen in all xenograft models

5、 tested5101520253035DaysDays afterafter treatmenttreatmentKI-12-0073 RCC PDXTumorTumor volumevolume(mm(mm3 3)VehicleVehicleCabozantinibCabozantinibKOKO-2806+2806+c cabozantinibabozantinibVHL wt and VHL null xenograft modelsCabozantinibCabozantinibKOKO-2806+2806+cabozantinibcabozantinibSLIDE DIMENSIO

6、NS SHOULD FOLLOW 16:9 RATIOKOKO-2806 enhances the anti2806 enhances the anti-angiogenic activity angiogenic activity of cabozantinib in RCC xenograftsof cabozantinib in RCC xenografts246810%CD31-positivep 0.0001012304%NG2-positivep=0.0115NG2(pericyte)CD31(endothelial cell)VehicleCabozantinibKO-2806C