Synthetic lethality between HER2 and transaldolase in intrinsically resistant HER2-positive breast cancers.

Ding, Yi

Gong, Chang

Huang, De

Chen, Rui

Sui, Pinpin

Lin, Kevin H

Liang, Gehao

Yuan, Lifeng

Xiang, Handan

Chen, Junying

Yin, Tao

Alexander, Peter B

Wang, Qian-Fei

Song, Er-Wei

Li, Qi-Jing

Wood, Kris C

Wang, Xiao-Fan

2022-12-01T14:41:07Z

2022-12-01T14:41:07Z

2018-10

2022-12-01T14:41:06Z

Intrinsic resistance to anti-HER2 therapy in breast cancer remains an obstacle in the clinic, limiting its efficacy. However, the biological basis for intrinsic resistance is poorly understood. Here we performed a CRISPR/Cas9-mediated loss-of-function genetic profiling and identified TALDO1, which encodes the rate-limiting transaldolase (TA) enzyme in the non-oxidative pentose phosphate pathway, as essential for cellular survival following pharmacological HER2 blockade. Suppression of TA increases cell susceptibility to HER2 inhibition in two intrinsically resistant breast cancer cell lines with HER2 amplification. Mechanistically, TA depletion combined with HER2 inhibition significantly reduces cellular NADPH levels, resulting in excessive ROS production and deficient lipid and nucleotide synthesis. Importantly, higher TA expression correlates with poor response to HER2 inhibition in a breast cancer patient cohort. Together, these results pinpoint TA as a novel metabolic enzyme possessing synthetic lethality with HER2 inhibition that can potentially be exploited as a biomarker or target for combination therapy.

10.1038/s41467-018-06651-x

2041-1723

2041-1723

https://hdl.handle.net/10161/26259

eng

Springer Science and Business Media LLC

Nature communications

10.1038/s41467-018-06651-x

Cell Line, Tumor

Humans

Breast Neoplasms

NADP

Transaldolase

Receptor, erbB-2

Cell Death

Drug Resistance, Neoplasm

Female

Pentose Phosphate Pathway

Genetic Testing

HEK293 Cells

CRISPR-Cas Systems

Metabolic Flux Analysis

Synthetic Lethal Mutations

Lapatinib

Synthetic lethality between HER2 and transaldolase in intrinsically resistant HER2-positive breast cancers.

Journal article

Li, Qi-Jing|0000-0002-0542-9784

Wood, Kris C|0000-0002-5887-2253

4274

1

Duke

School of Medicine

Basic Science Departments

Institutes and Centers

Cell Biology

Immunology

Pharmacology & Cancer Biology

Duke Cancer Institute

Institutes and Provost's Academic Units

Initiatives

Duke Innovation & Entrepreneurship

Published

9