BRCA1-deficient Breast Cancer Cell Lines Are Resistant to MEK Inhibitors and Show Distinct Sensitivities to 6-thioguanine

Overview

Journal Sci Rep

Specialty Science

Date 2016 Jun 18

PMID 27313062

Citations 14

Authors

Yuexi Gu

Mikko Helenius

Kristiina Vaananen

Daria Bulanova

Jani Saarela

Anna Sokolenko

John Martens

Evgeny Imyanitov

Sergey Kuznetsov

Affiliations

Soon will be listed here.

Abstract

Germ-line or somatic inactivation of BRCA1 is a defining feature for a portion of human breast cancers. Here we evaluated the anti-proliferative activity of 198 FDA-approved and experimental drugs against four BRCA1-mutant (HCC1937, MDA-MB-436, SUM1315MO2, and SUM149PT) and four BRCA1-wild-type (MDA-MB-231, SUM229PE, MCF10A, and MCF7) breast cancer cell lines. We found that all BRCA1-mutant cell lines were insensitive to inhibitors of mitogen-activated protein kinase kinase 1 and 2 (MEK1/2) Selumetinib and Pimasertib in contrast to BRCA1-wildtype control cell lines. However, unexpectedly, only two BRCA1-mutant cell lines, HCC1937 and MDA-MB-436, were hypersensitive to a nucleotide analogue 6-thioguanine (6-TG). SUM149PT cells readily formed radiation-induced RAD51-positive nuclear foci indicating a functional homologous recombination, which may explain their resistance to 6-TG. However, the reason underlying 6-TG resistance of SUM1315MO2 cells remains unclear. Our data reveal a remarkable heterogeneity among BRCA1-mutant cell lines and provide a reference for future studies.

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