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

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.

SUBMITTER: Ding Y

PROVIDER: S-EPMC6189078 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Ding Yi Y Gong Chang C Huang De Chen Rui R Sui Pinpin P Lin Kevin H KH Liang Gehao G Yuan Lifeng L Xiang Handan H Chen Junying J Yin Tao T Alexander Peter B PB Wang Qian-Fei QF Song Er-Wei EW Li Qi-Jing QJ Wood Kris C KC Wang Xiao-Fan XF

Nature communications 20181015 1

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 increas ...[more]

PMID: 30323337

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Project description:Background and objectiveBreast cancer (BC) is currently the most frequently diagnosed cancer and the primary cause of cancer-related death among women worldwide. Human epidermal growth factor receptor type 2 (HER2)-positive BC accounts for 14.5-15% of all BCs, with a relatively poor prognosis. Neoadjuvant therapy (NAT) has become a preferred treatment option for HER2+ BCs. With the continuous emergence of various clinical trials and new treatment concepts in BC, the NAT model has changed from chemotherapy alone to the neoadjuvant combination of anti-HER2-targeted therapy with chemotherapy, neoadjuvant endocrine therapy, and so on. Therefore, an up-to-date review is needed to inform the selection of NAT strategies for HER2+ BCs.MethodsThis review was administrated with literature from the PubMed database. Manuscripts were searched using the following keywords: "neoadjuvant" or "preoperative", "breast cancer" or "breast neoplasm", "HER2+" or "HER2-positive", titles and abstracts were screened and evaluated independently by two authors. Information relating to the efficacy and safety profile of NAT for patients with HER2+ BCs were included and analyzed qualitatively. Only English-language articles were included.Key content and findingsThis review discusses the neoadjuvant situation for the surgical management of HER2-positive BCs around the world. In this paper, we describe the efficacy assessment of NAT, analyze clinical effect and toxicity of chemotherapy, and targeted therapy, including monoclonal antibody, tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), and other neoadjuvant treatments in HER2+ BC. The data shows while overall survival is the standard endpoint for efficacy, pathological complete response have been implemented more and more frequently in clinical trials for its convenience. Dual-targeted therapy plus chemotherapy exhibited favorable efficacy in most cases, meanwhile other treatment strategies such as combinations without chemotherapy or including CDK4/6 agents may be applicable in specific situation.ConclusionsAs an important part of BC treatment, NAT is lingering in the stage of continuous development, especially for patients with HER2-positive BC. The challenges we are facing today in this field are dose de-escalation without reducing efficacy and choose suitable combination of agents in clinical practice. Moreover, new biomarkers are warrant for individualize treatment.

Dataset Information

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

Publications

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

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