GLI1 Inhibitor SRI-38832 Attenuates Chemotherapeutic Resistance by Downregulating NBS1 Transcription in BRAFV600E Colorectal Cancer.

Ruowen Zhang,Justin T Avery,Vijaya Sambandam,Mark J Suto,Rebecca J Boohaker,Bo Xu,Theresa H Nguyen,Jinlu Ma

doi:10.3389/fonc.2020.00241

Abstract

Resistance to radiation and chemotherapy in colorectal cancer (CRC) patients contribute significantly to refractory disease and disease progression. Herein, we provide mechanistic rationale for acquired or inherent chemotherapeutic resistance to the anti-tumor effects of 5-fluorouracil (5-FU) that is linked to oncogenic GLI1 transcription activity and NBS1 overexpression. Patients with high levels of GLI1 also expressed high levels of NBS1. Non-canonical activation of GLI1 is driven through oncogenic pathways in CRC, like the BRAFV600E mutation. GLI1 was identified as a novel regulator of NBS1 and discovered that by knocking down GLI1 levels in vitro, diminished NBS1 expression, increased DNA damage/apoptosis, and re-sensitization of 5-FU resistant cancer to treatment was observed. Furthermore, a novel GLI1 inhibitor, SRI-38832, which exhibited pharmacokinetic properties suitable for in vivo testing, was identified. GLI1 inhibition in a murine BRAFV600E variant xenograft model of CRC resulted in the same down-regulation of NBS1 observed in vitro as well as significant reduction of tumor growth/burden. GLI1 inhibition could therefore be a therapeutic option for 5-FU resistant and BRAFV600E variant CRC patients.

Highlights

Colorectal Cancer (CRC) is ranked as the third most prevalent and deadly tumor type in the United States, with ∼145,000 newly diagnosed cases and upwards of 50,000 deaths attributed to the disease in 2018 alone [1]
For patients at Stage TIII disease, the average GLI1 and Nijmegen breakage syndrome-1 (NBS1) expression was found to be elevated when compared to the average patient cohort, while the patients in NI-II Stage showed lower than average expression
These data strongly indicate that patients with elevated GLI1 and NBS1 expression had a poorer prognosis than patients with reduced protein expression when given the same treatment

Summary

Introduction

Colorectal Cancer (CRC) is ranked as the third most prevalent and deadly tumor type in the United States, with ∼145,000 newly diagnosed cases and upwards of 50,000 deaths attributed to the disease in 2018 alone [1]. Genetic analysis of biopsied tissue from CRC patients indicates that a significant subset, ∼10%, expressed oncogenic BRAF [2, 3]. Within this subset, patients bearing a missense mutation within BRAF at position V600E faced significantly shorter overall survival and an 80% mortality rate [4]. Attempts to target this BRAFV600E variant with the single-agent kinase inhibitor Vemurafenib was found to be wholly ineffective with a

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