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

Yi Ding, Chang Gong, De Huang, Rui Chen, Pinpin Sui, Kevin H. Lin, Gehao Liang, Lifeng Yuan, Handan Xiang, Junying Chen, Tao Yin, Peter B. Alexander, Qian Fei Wang, Er Wei Song, Qi Jing Li, Kris C. Wood, Xiao Fan Wang

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number4274
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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