Enhanced efficacy of sitravatinib in metastatic models of antiangiogenic therapy resistance

PloS One
Melissa DolanJohn M L Ebos

Abstract

Tyrosine kinase inhibitors (TKIs) that primarily target angiogenesis are approved to treat several cancers in the metastatic setting; however, resistance is common. Sequential treatment or 'switching' from one TKI to another following failure can be effective, but predicting which drugs will have cross-over sensitivity remains a challenge. Here we examined sitravatinib (MGCD516), a spectrum-selective TKI able to block MET, TAM (TYRO3, AXL, MerTK) and multiple receptor families (including PDGFRs, VEGFRs, and Ephs). Transcriptomic analysis of several mouse and human cell lines revealed diverse molecular changes after resistance to two TKIs (sunitinib and axitinib) with multiple sitravatinib targets found to be upregulated. Sitravatinib treatment in vitro resulted in enhanced anti-proliferative effects in resistant cells and was improved compared to TKIs with similar target profiles. In vivo, primary tumor growth inhibition after sitravatinib treatment in mice was enhanced in resistant tumors and metastasis suppression improved when tumors were surgically removed. Together, these results suggest that the diverse and often inconsistent compensatory signaling mechanisms found to contribute to TKI resistance may paradoxically improve...Continue Reading

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Citations

Sep 22, 2020·Expert Opinion on Drug Delivery·Archana UpadhyaAmbikanandan Misra
Mar 29, 2020·Signal Transduction and Targeted Therapy·Yuan-Hong XieJing-Yuan Fang
Jan 26, 2021·Molecular Biology Reports·Mohd MugheesSaima Wajid
Apr 17, 2020·Signal Transduction and Targeted Therapy·Yuan-Hong XieJing-Yuan Fang

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Datasets Mentioned

BETA
GSE132568

Methods Mentioned

BETA
surgical resection
FCS
protein assay
xenograft

Clinical Trials Mentioned

NCT03015740

Software Mentioned

STAR
R
Image Lab
edgeR
RSEM
RSeQC
ChemiDoc System
FASTQC
Bioconductor package
FACSDiva

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