Integrating mechanisms of response and resistance against the tubulin binding agent Eribulin in preclinical models of osteosarcoma.

Valerie B Sampson,Robert W Mason,Pratima U Patil,Wendong Zhang,Richard Gorlick,Erika George,Nancy S Vetter,Edward A Kolb

doi:10.18632/oncotarget.13358

Abstract

Osteosarcoma is the most frequently occurring bone cancer in children and adolescents. Unfortunately, treatment failures are common. Eribulin is a synthetic microtubule inhibitor that has demonstrated activity in preclinical osteosarcoma models. The effects of eribulin were evaluated in two human osteosarcoma cell lines as well as in eribulin-sensitive and -resistant osteosarcoma xenograft tumors of the Pediatric Preclinical Testing Program (PPTP) by characterizing cell viability, microtubule destabilization, mitotic arrest and mechanism of cell death. Eribulin demonstrated cytotoxic activity in vitro, through promotion of microtubule dynamic instability, arrest of cells in the G2/M phase, mitotic catastrophe and cell death. The microtubule-destabilizing protein stathmin-1 (STMN1) was coimmunoprecipitated with the cyclin-dependent kinase inhibitor p27 indicating that these cytoplasmic complexes can protect cells from the microtubule destabilizing effect of eribulin. Increased tumoral expression of P-glycoprotein (P-gp) and TUBB3 were also associated with lower drug sensitivity. In summary, eribulin successfully blocked cells in G2/M phase but interfered with mitochondria activity to inhibit proteins involved in apoptosis. Understanding the complex and inter-related mechanisms involved in the overall drug response to eribulin may help in the design of therapeutic strategies that enhance drug activity and improve benefits of eribulin in pediatric patients with osteosarcoma.

Highlights

Osteosarcoma is the most frequent primary bone sarcoma that typically occurs in children and adolescents between 10 - 20 years of age [1]
We examined the effects of eribulin on the proliferation of two osteosarcoma cell lines, SaOS and 143B
Given the robust preclinical activity of microtubule inhibitors in www.impactjournals.com/oncotarget the Pediatric Preclinical Testing Program (PPTP) osteosarcoma panel, we investigated treatment effects on multiple processes that are sensitive to the loss of microtubule function

Summary

Introduction

Osteosarcoma is the most frequent primary bone sarcoma that typically occurs in children and adolescents between 10 - 20 years of age [1]. Current multimodal therapy consisting of surgery with pre- and post– operative chemotherapy, achieves a 5-year survival rate of approximately 60 - 70% for non-metastatic high grade osteosarcoma patients [2, 3], while patients who present with metastatic disease at diagnosis have a 10 - 30% survival rate [4]. Chemotherapy agents that demonstrate anti-tumor activity in osteosarcoma include cisplatin, doxorubicin, ifosfamide and high dose-methotrexate [5]. Treatment of existing metastatic disease and prevention of metastatic spread remain among the top challenges to increase long-term survival of patients. New therapeutic approaches and treatment strategies are being investigated to improve outcomes for patients with cancers that are resistant to current therapy

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