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.
Highlights
Intrinsic resistance to anti-HER2 therapy in breast cancer remains an obstacle in the clinic, limiting its efficacy
Isotopic label-based metabolic profiling indicates that HER2 inhibition systematically alters cellular metabolism, such that metabolic flux through the nonoxidative phosphate pathway (PPP) becomes essential for cancer cells to survive lapatinib treatment
In order to focus on the clinical problem of intrinsic drug resistance, we used MDA-MB-361 cells, which are derived from a HER2-amplified metastatic breast cancer patient and insensitive to lapatinib[34]
Summary
Intrinsic resistance to anti-HER2 therapy in breast cancer remains an obstacle in the clinic, limiting its efficacy. These studies provide insight into antiHER2 resistance mechanisms and possible targets to be exploited pharmacologically, many were performed using acquired resistance models derived by chronically treating cells with increasing doses of HER2 inhibitors Those models may not be relevant to the 20% of metastatic HER2-positive breast cancer patients who exhibit intrinsic resistance, failing to respond to anti-HER2 therapy from the beginning[12]. In order to discover mechanisms mediating intrinsic antiHER2 resistance and identify novel therapeutic targets, we performed functional CRISPR/Cas[9] genetic profiling in MDAMB-361 cells, which are intrinsically resistant to HER2 inhibition From this screen, we identified the metabolic enzyme transaldolase (TA), which catalyzes the rate-limiting step in the non-oxidative PPP, as essential for cells to survive under lapatinib treatment. Because TA expression effectively stratifies the outcome of HER2-targeted therapy in breast cancer patients, TA may represent a novel biomarker and new target for the treatment of recalcitrant HER2-positive breast cancer
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