Predictive value of MRP-1 in localized high-risk soft tissue sarcomas: a translational research associated to ISG-STS 1001 randomized phase III trial.

MRP-1 is implicated in multidrug resistance and was described as prognostic in high-risk soft-tissue sarcoma (STS) patients in a previous study. The current research aimed to validate MRP-1 prognostic/predictive value in localized sarcomas treated with anthracyclines plus ifosfamide within the ISG-1001 phase III study. Additionally, the inhibitory activity on MRP-1 was investigated in preclinical studies to identify new combinations able to increase the efficacy of standard chemotherapy in STS. MRP-1 expression was assessed by immunohistochemistry in tissue microarrays from STS patients and tested for correlation with disease-free survival (DFS) and overall survival (OS). In vitro studies tested the efficacy of MRP-1 inhibitors (nilotinib, ripretinib, selumetinib and avapritinib) in sarcoma cell lines. The effect of combinations of the most active MRP-1 inhibitors and chemotherapy was measured based on apoptosis. MRP-1 was evaluable in 231 out of 264 cases who entered the study. MRP-1 expression (strong intensity) was independently associated with worse DFS [HR=1.78 (95%CI, 1.11-2.83)], p=0.016, in the multivariate analysis, with a trend for a worse OS [HR=1.78 (95%CI, 0.97-3.25)], p=0.062. In vitro studies showed that the addition of MRP-1 inhibitors (nilotinib or avapritinib) to doxorubicin plus palifosfamide, significantly increased cell death in SK-UT-1 and CP0024 cell lines. MRP-1 is an adverse predictive factor in localized high-risk STS patients treated with neoadjuvant anthracyclines plus ifosfamide followed by surgery. In vitro findings support the clinical assessment of the combination of chemotherapy and MRP-1 inhibitors as a promising strategy to overcome the drug ceiling effect for chemotherapy.