Abstract
Sunitinib improves the outcomes of patients with solitary fibrous tumours (SFTs). The aim of this study was to investigate and contextualise sunitinib-induced morpho-functional changes in order to gain insights into the drug's mechanism of action.To this end, four surgical specimens obtained from two sunitinib-responsive patients with malignant SFT, and one primary cell culture obtained from fresh tumoral tissue and its stabilised cell line, were studied by means of immunohistochemistry, bright field in situ hybridisation, immunofluorescence/confocal microscopy, and biochemistry.The post-sunitinib surgical samples were characterised by two biologically relevant morpho-functional changes: clear areas and necrotic foci. The first were associated with the attenuation/loss of PDGFRB expression and decreased mTOR signalling, and corresponded to a pathological response. The second were associated with the over-expression of PDGFRB and VEGFA, strong mTOR signalling activation, and the appearance of HIF1α expression, hallmarks of pathological progression. The analysis clearly showed that sunitinib reduces the vascular supply network and inhibits tumoral cells. It also either induces autophagy, thus favouring drug response, or impairs autophagy as a result of lysosome sequestration, thus favouring disease progression. These distinct autophagic events were associated with different myeloid immune contextures. Finally, we also found that PDGFRB is one of the components of a complex that includes Beclin 1 and VPS34.The results of these tissue-based analyses provide new insights into sunitinib's mechanism of action in SFT patients.
Highlights
Solitary fibrous tumours (SFTs) are ubiquitous but rare soft tissue sarcomas bearing the NAB2/STAT6 fusion gene that are characterised by a spectrum of “usual”, “malignant” and “dedifferentiated” variants [1,2,3]
In order to make a thorough review of the changes induced by sunitinib, and their meaning in terms of response/ resistance, we extensively examined three post-sunitinib surgical specimens obtained from two sunitinib-responsive patients with malignant solitary fibrous tumours (SFTs), and evaluated the characteristics of one tumour tissue specimen obtained from one of the patients before sunitinib treatment
Given that: i) autophagy preserves cell homeostasis, and shapes cell immunity and influences the differentiation and activation of myeloid and lymphoid cells [30]; ii) sunitinib has strong immunomodulating effects on the periphery and tumour sites of SFTs [15]; iii) our stabilised cell line readouts suggested the induction of non-protective autophagy, which has been found to elicit a local immune response in vivo [17]; and iv) the necrotic/progressive foci in our surgical specimens showed the increased VEGFA availability and the expression of HIF1α, both of which are known to mediate immunosuppressive function [31,32,33], we investigated the distribution of immune-related cells in post-sunitinib lesions by comparing the samples characterised by clear/ responsive areas with those characterised by necrotic/ progressive foci
Summary
Solitary fibrous tumours (SFTs) are ubiquitous but rare soft tissue sarcomas bearing the NAB2/STAT6 fusion gene that are characterised by a spectrum of “usual”, “malignant” and “dedifferentiated” variants [1,2,3]. Advanced SFTs are sensitive to sunitinib [4,5,6,7,8], the rare dedifferentiated variant, which is currently regarded as a genetically reprogrammed, highly instable SFT [9], seems to be less sensitive to anti-angiogenic agents [4, 10] Other drugs such as bevacizumab, sorafenib, pazopanib and IGF1R inhibitors [5, 6, 11,12,13,14] have proved to be efficacious in treating advanced SFTs, but the complementary nature of the receptor tyrosine kinases (RTKs) activated in SFTs and the RTKs inhibited by sunitinib [5] suggests that sunitinib should be more effective. The antitumoral efficacy of sunitinib is transient, and it can be hypothesised that the reduced blood flow and autophagy promoted by prolonged treatment act as adaptive mechanisms that lead to resistance [16]
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