Defining the mechanisms of multi-target tyrosine kinase inhibitor resistance in soft tissue sarcoma

Abstract

Soft tissue sarcomas (STS) are a rare, heterogeneous, and challenging group of cancers to treat effectively. The approval of pazopanib, as well as promising clinical trial data for a number of other multi-target tyrosine kinase inhibitors (TKI), has demonstrated that this family of drug could be employed in the effective treatment of a number of advanced STS subtypes. However, treatment of advanced STS patients with multi-target TKIs has been shown to universally result in drug resistance, either through an intrinsic resistance or an acquired resistance after an initial response. The mechanisms of multi-target TKI resistance in STS are currently poorly understood and, as a result, STS patients currently lack effective salvage therapies. There is therefore a clinically unmet need to better understand mechanisms of multi-target TKI resistance in STS. This increased knowledge will allow for the development of novel treatment strategies to combat the emergence of TKI resistance, as well as salvage therapies that could be employed to treat TKI-resistant disease. In order to answer these questions, this project employed patient-derived xenograft (PDX)-derived STS cells as models of acquired and intrinsic pazopanib resistance and these were subjected to small molecule inhibitor screens. The multi-target TKI dasatinib was found to be an effective salvage therapy in pazopanib-resistant STS cells, mediated through inhibition of the Src signalling pathway. Building on this, I attempted to establish upstream mediators of Src signalling activity in Src-dependent, pazopanib-resistant STS and subsequently identified integrin signalling as a potential upstream regulator. Additionally, I determined that the KTIs erdafitinib and ponatatinib were effective in the first-line treatment of the A204 and G402 malignant rhabdoid tumour (MRT) cell lines characterised by co-activation of PDGFRa and FGFR1. Further to this, in A204 models harbouring multi-target TKI resistance towards pazopanib, regorafenib, sitravatinib, and anlotinib, erdafitinib and ponatinib were also found to be effective salvage therapies. Interestingly, the acquisition of sitravatinib resistance resulted in the emergence of collateral sensitivity to selective FGFR inhibition by infigratinib. Upon re-acquisition of resistance to infigratinib, I have also elucidated further-line strategies that can be utilised to control disease progression. Through these means, I have nominated a number of treatment strategies that could be employed in order to control disease progression and resistance in MRT, an aggressive paediatric STS subtype.