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BackgroundIncreasing studies implicate cancer stem cells CSCs as the source of resistance and relapse following conventional cytotoxic therapies Few studies have examined the response of CSCs to targeted therapies such as tyrosine kinase inhibitors TKIs We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action anti-proliferative vs anti-angiogenic MethodsWe exposed human sarcoma cell lines to sorafenib regorafenib and pazopanib and assessed cell viability and expression of CSC markers ALDH CD24 CD44 and CD133 We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy We exposed dissociated primary sarcoma tumors to sorafenib regorafenib and pazopanib and we used tissue microarray TMA and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib Parametric and non-parametric statistical analyses were performed as appropriate ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines P 0 05 with a corresponding 1 4 2 8 fold increase in ALDHbright cells from baseline P 0 05 In contrast we observed negligible effects on viability and CSC sub-populations with pazopanib At low doses there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated In vivo sorafenib improved median survival by 11 days P 0 05 but enriched ALDHbright cells 2 5 2 8 fold P 0 05 Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells P 0 05 Again negligible effects from pazopanib were observed TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen P 0 05 whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells P 0 05 ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations

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Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcom...