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

Yi Ding, Chang Gong, Huang De, 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 () and Xiao-Fan Wang ()
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Yi Ding: Duke University Medical Center
Chang Gong: Sun Yat-Sen University
Huang De: Duke University Medical Center
Rui Chen: Duke University Medical Center
Pinpin Sui: Chinese Academy of Sciences
Kevin H. Lin: Duke University Medical Center
Gehao Liang: Sun Yat-Sen University
Lifeng Yuan: Duke University Medical Center
Handan Xiang: Duke University Medical Center
Junying Chen: Sun Yat-Sen University
Tao Yin: Duke University Medical Center
Peter B. Alexander: Duke University Medical Center
Qian-Fei Wang: Chinese Academy of Sciences
Er-Wei Song: Sun Yat-Sen University
Qi-Jing Li: Duke University Medical Center
Kris C. Wood: Duke University Medical Center
Xiao-Fan Wang: Duke University Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06651-x

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