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Genome-wide synthetic lethal screen unveils novel CAIX – NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors.

ABSTRACT: Hypoxia is an important clinicopathological feature of solid tumours that limits response to therapy. Carbonic Anhydrase IX (CAIX) is a hypoxia-induced, pH regulator that has emerged as a viable therapeutic target. Targeting CAIX has demonstrated promise in difficult to treat preclinical models of breast pancreatic, melanoma and brain cancers when combined with chemotherapy and immunotherapy, however resistance ultimately develops and this mechanism is unclear. Here we used an unbiased genome-wide synthetic lethal CRISPR knock-out screen in basal breast cancer cells to identify co-vulnerabilities and mechanisms of compensation for CA9 loss. We identified a redox homeostasis network containing thioredoxin and the iron-sulfur cluster enzyme, cysteine desulfurase, NFS1, indicative of the critical importance of CAIX in this role.

ORGANISM(S): Homo sapiens

PROVIDER: GSE167481 | GEO | 2021/08/28

REPOSITORIES: GEO

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Project description:Breast cancer is a heterogeneous disease classified into 3 major subtypes based on the presence or absence of molecular markers for oestrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor-2 (Her2) . Hormone receptor-positive BC (ER+, PR+ and Her-2-), accounts for approximately 70% of patients. Patients with ER- BC account for approximately 30 % of all cases and commonly have a worse prognosis than ER+ patients (9). However, a significant proportion of ER- cases have good outcomes and could potentially benefit from a less aggressive therapy. Triple negative breast cancer (TNBC, ER-, PR- and Her-2-) accounts for approximately 15% of breast cancers and has the poorest outcomes. An hypoxic microenvironment is an important intrinsic component of solid tumours that can result in rapid proliferation of cancer cells and is associated with the lack of oxgyen and abnormal tumour blood vessels. Hypoxia stimulates the hypoxia inducible factor-1α (HIF-1α) that transactivates genes associated with angiogenesis, tumour growth, metastasis, metabolic reprogramming, and treatment resistance. HIF-1α is recognised to induce the expression of carbonic anhydrase IX (CAIX), an enzyme that has been attributed a central role in pH regulation and cancer progression and is particularly pronounced in peri necrotic tumour areas, high-grade BCs. The adaption to hypoxia is governed by multiple transcriptional and post-transcriptional changes in gene expression. Up to 1.5 % of the human genome is estimated to be transcriptionally responsive to hypoxia. Genes and pathways which have been identified as being responsive to hypoxia may have the potential to be used as prognostic or predictive markers, and furthermore, can help identify novel therapeutic targets. The aim of the present study was to gain a better understanding of the transcriptomic and protein pathways associated with CAIX in ER- BC to identify potential therapeutic targets against this aggressive phenotype.

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Genome-wide synthetic lethal screen unveils novel CAIX – NFS1/xCT axis as a targetable vulnerability in hypoxic solid tumors.

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