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Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
Synthetic lethality between HER2 and transaldolase in intrinsically resistant HER2-positive breast cancers
Yi Ding1, Chang Gong2, De Huang1
1Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, 27705, USA.
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.
Insights
Intrinsic resistance to HER2-targeted therapy in breast cancer is a clinical challenge. Researchers identified transaldolase (TALDO1) as a key enzyme, revealing its potential as a biomarker or therapeutic target for overcoming resistance.
Area of Science:
- Oncology
- Metabolism
- Molecular Biology
Background:
- Intrinsic resistance to anti-HER2 therapy limits treatment efficacy in breast cancer.
- The underlying biological mechanisms of this resistance are not well understood.
Purpose of the Study:
- To identify novel targets and pathways involved in intrinsic resistance to HER2-targeted therapy.
- To elucidate the role of metabolic enzymes in cellular response to HER2 blockade.
Main Methods:
- CRISPR/Cas9-mediated loss-of-function genetic screening was employed.
- Functional assays were performed in intrinsically resistant breast cancer cell lines with HER2 amplification.
- Cellular NADPH levels, reactive oxygen species (ROS), and synthesis of lipids and nucleotides were measured.
Main Results:
- Transaldolase (TALDO1), a key enzyme in the pentose phosphate pathway, was identified as essential for survival under HER2 blockade.
- Suppression of TALDO1 increased sensitivity to HER2 inhibition in resistant cell lines.
- Combined TALDO1 depletion and HER2 inhibition led to reduced NADPH, increased ROS, and impaired lipid/nucleotide synthesis.
- Elevated TALDO1 expression correlated with poor response to HER2-targeted therapy in patients.
Conclusions:
- Transaldolase (TALDO1) is a critical metabolic enzyme involved in intrinsic resistance to HER2-targeted therapy.
- TALDO1 exhibits synthetic lethality with HER2 inhibition, suggesting its potential as a therapeutic target.
- TALDO1 may serve as a predictive biomarker for response to HER2-targeted therapies in breast cancer.
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