Eribulin inhibits growth of cutaneous squamous cell carcinoma cell lines and a novel patient-derived xenograft

Abstract

Advanced cutaneous squamous cell carcinoma (cSCC) is treated with chemotherapy and/or radiotherapy, but these typically fail to achieve satisfactory clinical outcomes. There have been no preclinical studies to evaluate the effectiveness of eribulin against cSCC. Here, we examine the effects of eribulin using cSCC cell lines and a novel cSCC patient-derived xenograft (PDX) model. In the cSCC cell lines (A431 and DJM-1 cells), eribulin was found to inhibit tumor cell proliferation in vitro as assessed by cell ATP levels. DNA content analysis by fluorescence-activated cell sorting (FACS) showed that eribulin induced G2/M cell cycle arrest and apoptosis. In xenograft models of cSCC cell lines, the administration of eribulin suppressed tumor growth in vivo. We also developed a cSCC patient-derived xenograft (PDX) which reproduces the histological and genetic characteristics of a primary tumor. Pathogenic mutations in TP53 and ARID2 were detected in the patient’s metastatic tumor and in the PDX tumor. The cSCC-PDX responded well to the administration of eribulin and cisplatin. In conclusion, the present study shows the promising antineoplastic effects of eribulin in cSCC. Also, we established a novel cSCC-PDX model that preserves the patient’s tumor. This PDX could assist researchers who are exploring innovative therapies for cSCC.

Ex vivo therapeutic screening of metastatic cSCC: A review of methodological considerations for clinical implementation

“…The lymph node metastasis from a 69‐year old Japanese male with a history of smoking was subcutaneously implanted into female NOD/ShiJic‐ scid Jcl mice, and subsequent tumours transplanted into further generations of mice. This model demonstrated that 1.5 mg/kg/week administration of the chemotherapeutic eribulin was as effective as the clinically‐utilised cisplatin in suppressing cSCC tumour growth 32 . Importantly, the PDX tumours and resultant primary cell lines retained key driver mutations observed in the patient's tumours, including those in tumour suppressors TP53 and ARID2 .…”

“…This model demonstrated that 1.5 mg/kg/week administration of the chemotherapeutic eribulin was as effective as the clinically-utilised cisplatin in suppressing cSCC tumour growth. 32 Importantly, the PDX tumours and resultant primary cell lines retained key driver mutations observed in the patient's tumours, including those in tumour suppressors TP53 and ARID2.…”

“…This is a critical shortcoming in metastatic cSCC research given the importance of immune involvement in cSCC behaviour 43 . While patient‐derived xenografts do retain the heterogeneity and gene expression profiles observed in the tumours from which they are derived, they are yet to be translated to immunocompetent mice in the context of metastatic cSCC 32 . As such, the immune interactions expected in human systems cannot yet be reflected using such in vivo models either.…”

“…The only other model derived from metastatic cSCC tissue is a patient-derived xenograft (PDX). 32 The lymph node metastasis from a 69-year old Japanese male with a history of smoking was subcutaneously implanted into female NOD/ShiJic-scidJcl mice, and subsequent tumours transplanted into further generations of mice. This model demonstrated that 1.5 mg/kg/week administration of the chemotherapeutic eribulin was as effective as the clinically-utilised cisplatin in suppressing cSCC tumour growth.…”

“…The only other model derived from metastatic cSCC tissue is a patient‐derived xenograft (PDX) 32 . The lymph node metastasis from a 69‐year old Japanese male with a history of smoking was subcutaneously implanted into female NOD/ShiJic‐ scid Jcl mice, and subsequent tumours transplanted into further generations of mice.…”