Abstract 4350: Low frequencies of SF3B1 mutations indicate SF3B1 inhibitor as a novel moleculartargeted drug for colorectal cancer.

Abstract

Purpose: FR901464 (FR) is an antitumor agent that specifically binds to and inhibits the function of splicing factor 3B subunit 1 (SF3B1). Higher frequencies of SF3B1 gene mutations and their relevance to cancer progression have been shown in studies of hematological malignancies. We assessed the frequencies of SF3B1 gene mutations in colorectal cancer (CRC) and the correlation of SF3B1 mutations and FR sensitivity in CRC. Experimental Design: We measured FR sensitivity in CRC cell lines to establish FR-resistant clones and performed DNA sequencing of all 25 SF3B1 exons in nine CRC cell lines, FR-resistant clones, and 16 CRC patients. On the basis our results, we performed further DNA sequencing in 80 CRC patients. Results: The FR IC50 values in all CRC cell lines were < 1ng/ml. Six FR-resistant clones were established: three from DLD1, two from HCT116, and one from LoVo cells. The FR IC50 of the FR-resistant clones was > 500-fold greater than that of their parental cells, although the IC50 of oxaliplatin or 5-fuluorouracil were the same. We found nonsense mutations in exon 10 of DLD1 cells and no significant mutations in the other samples. All the FR-resistant clones had the missense mutations in codon 1073 of exon 22. We found no mutation in exons 10, 22, and 12-15, which were previously reported in hematological malignancies in 80 CRC patients. Conclusion: Our data indicated the usefulness of the SF3B1 inhibitor as a novel molecular targeted drug for CRC and the other malignancies without codon 1073 mutations. Citation Format: Tomoki Yamano, Hidenori Nakajima, Satoshi Tsuda, Shuji Kubo, Mie Hamanaka, Masayoshi Kobayashi, Daisuke Yamagishi, Takashi Kuno, Kiyoshi Tsukamoto, Astuko Tamamoto, Masafumi Noda, Nagahide Matsubara, Dave SB Hoon, Naohiro Tomita. Low frequencies of SF3B1 mutations indicate SF3B1 inhibitor as a novel moleculartargeted drug for colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4350. doi:10.1158/1538-7445.AM2013-4350