Oncotarget

Research Papers:

Splicing modulator FR901464 is a potential agent for colorectal cancer in combination therapy

Tomoki Yamano _, Shuji Kubo, Aya Yano, Tomoko Kominato, Shino Tanaka, Masataka Ikeda, Naohiro Tomita

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Oncotarget. 2019; 10:352-367. https://doi.org/10.18632/oncotarget.26564

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Abstract

Tomoki Yamano1, Shuji Kubo2, Aya Yano1, Tomoko Kominato1, Shino Tanaka1, Masataka Ikeda1 and Naohiro Tomita1

1Division of Lower Gastrointestinal Surgery, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

2Laboratory of Molecular and Genetic Therapeutics, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan

Correspondence to:

Tomoki Yamano, email: yamanot@hyo-med.ac.jp

Keywords: SF3B1; splicing; modulator; colorectal cancer; combination

Received: April 12, 2018     Accepted: December 29, 2018     Published: January 08, 2019

ABSTRACT

FR901464 (FR) was first described as an anticancer drug and later identified as a modulator of splicing factor 3B subunit 1 (SF3B1). Although the effectiveness of splicing modulators has been investigated in colorectal cancer (CRC) cells, their usefulness in animal experiments has not been confirmed. The association of SF3B1 with CRC progression and the influence of FR on transcriptional activity in CRC has not been fully elucidated. FR showed strong cytotoxicity against CRC cell lines, SF3B1-mutated cancer cell lines, and human fibroblasts with IC50 values less than 1 ng/ml. FR-resistant clones derived from HCT116, DLD1, Lovo, and CT26 cells showed IC50 values greater than 100 ng/ml. SF3B1 sequencing demonstrated low frequencies of SF3B1 mutations in CRC and mutations in codon 1074 of exon 22 in all FR-resistant clones. Unlike hematological malignancies, SF3B1 expression was not associated with CRC progression. Although FR showed significant growth inhibition in a xenograft model of RKO cells, severe toxicity was also induced. These data indicated CRC might be a suitable target of FR unless toxicity occurs. Microarray analysis and real-time quantitative PCR demonstrated downregulation of genes associated with Fanconi anemia (BRCA1 and BRCA2) and 28 driver oncogenes. These data suggested combination treatment of FR with other anticancer drugs whose sensitivity is associated with genes affected by FR treatment. Combination treatment with PARP1 inhibitor olaparib, whose sensitivity was enhanced by BRCA 1/2 deficiency, showed synergistic effects in CRC cells. Our data indicates the potential of FR in combination therapy rather than monotherapy for CRC treatment.


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