Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy

Martínez-Sáez, Olga; Borau, P. Gajate; Alonso‐Gordoa, Teresa; Molina‐Cerrillo, Javier; Grande, Enrique

doi:10.1016/j.critrevonc.2017.01.013

Cited by 96 publications

(81 citation statements)

References 75 publications

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“…Indeed, HIF-1α has been linked with tumor suppressive functions in ccRCC [13], [14], while HIF-2α has been established as a dominant oncogenic driver of disease progression [15], [16], [17], [18]. These observations have supported efforts to develop small molecule antagonists of HIF-2α, which are currently being tested in clinical trials for the treatment of metastatic ccRCC [19], and will be discussed later.…”

Section: Genetics Of Ccrccmentioning

confidence: 99%

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Sanchez

Simon

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

118

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Clear cell renal cell carcinoma (ccRCC) is a malignancy characterized by deregulated hypoxia-inducible factor signaling, mutation of several key chromatin modifying enzymes, and numerous alterations in cellular metabolism. Pre-clinical studies have historically been limited to cell culture models, however, the identification of critical tumor suppressors and oncogenes from large-scale patient sequencing data has led to several new genetically engineered mouse models with phenotypes reminiscent of ccRCC. In this review, we summarize recent literature on these topics and discuss how they inform targeted therapeutic approaches for the treatment of ccRCC.

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Section: Genetics Of Ccrccmentioning

confidence: 99%

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Sanchez

Simon

2018

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

118

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“…One emerging theme of this cell state is dysregulated lipid metabolism. Clear cell renal cell carcinoma (ccRCC), the most frequent form of RCC, features by aberrant accumulation of glycogen and lipid droplets [6][7][8][9], whereas renal oncocytomas exhibit early loss of mitochondrial complex I genes, and stalled lipid b-oxidation [10,11]. While these metabolic alterations support cancer progression and promote resistance to immune surveillance and therapies [5,12], directly targeting the primary metabolic liabilities remains challenging due to complications from metabolic plasticity and systematic toxicity of available compounds [13,14].…”

Section: Introductionmentioning

confidence: 99%

HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma

Zou

Palte

Deik

et al. 2018

Preprint

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SUMMARYKidney cancers are characterized by extensive metabolic reprogramming and resistance to a broad range of anti-cancer therapies. By interrogating the Cancer Therapeutics Response Portal compound sensitivity dataset, we show that cells of clear-cell renal cell carcinoma (ccRCC) possess a lineage-specific vulnerability to ferroptosis that can be exploited by inhibiting glutathione peroxidase 4 (GPX4). Using genome-wide CRISPR screening and lipidomic profiling, we reveal that this vulnerability is driven by the HIF-2a-HILPDA pathway by inducing a polyunsaturated fatty acyl (PUFA)-lipid-enriched cell state that is dependent on GPX4 for survival and susceptible to ferroptosis. This cell state is developmentally primed by the HNF-1b-1-Acylglycerol-3-Phosphate O-Acyltransferase 3 (AGPAT3) axis in the renal lineage. In addition to PUFA metabolism, ferroptosis is facilitated by a phospholipid flippase TMEM30A involved in membrane topology. Our study uncovers an oncogenesis-associated vulnerability, delineates the underlying mechanisms and suggests targeting GPX4 to induce ferroptosis as a therapeutic opportunity in ccRCC.

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“…Thus, hypoxia‐inducible factor will be accumulated inside the tumor cell and form the heterodimer consisting of an oxygen‐sensitive α subunit (HIF‐1α and HIF‐2α) and a constitutively expressed β subunit aryl hydrocarbon receptor nuclear translocator (ARNT) . Recent studies indicated HIF‐2α played an essential oncogenic role in the development of pVHL‐defective ccRCC . Therefore, targeting HIF‐2 is currently deemed to be the most direct therapy of the treatment for ccRCC.…”

Section: Introductionmentioning

confidence: 99%

“…7,8 9 Recent studies indicated HIF-2α played an essential oncogenic role in the development of pVHL-defective ccRCC. 2,10 Therefore, targeting HIF-2 is currently deemed to be the most direct therapy of the treatment for ccRCC.…”

Section: Introductionmentioning

confidence: 99%

Exploring the inhibition mechanism on HIF‐2 by inhibitor PT2399 and 0X3 using molecular dynamics simulations

Sun

Wang

Zheng

et al. 2018

J of Molecular Recognition

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Targeting transcription factors HIF-2 is currently considered to be the most direct way for the therapy of clear cell renal cell carcinoma. The preclinical inhibitor PT2399 and artificial inhibitor 0X3 have been identified as promising on-target inhibitors to inhibit the heterodimerization of HIF-2. However, the inhibition mechanism of PT2399 and 0X3 on HIF-2 remains unclear. To this end, molecular dynamics (MD) simulations and molecular docking were applied to investigate the effects of 2 inhibitors on structural motifs and heterodimerization of HIF-2. Our simulation results reveal that the binding of inhibitors disrupts the crucial hydrogen bond and hydrophobic interactions of interdomain of HIF-2 heterodimer due to the local conformational changes of binding interface, confirming the hypothesis that the perturbation of few residues is sufficient to disrupt the heterodimerization of HIF-2. In addition, it can be found that PT2399 with dominant substituents (cyano, fluorine, sulfuryl, and hydroxyl) is more preferred than 0X3 as HIF-2 inhibitor and these substituents play a crucial role in involving more hydrogen bond interactions with residues of interface and then cause the larger structural change of protein. This study may provide a deeper atomic-level insight into the effect of on-target inhibitors on HIF-2 heterodimer, which is expected to contribute to further rational design of effective clear cell renal cell carcinoma drugs.

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Targeting HIF-2 α in clear cell renal cell carcinoma: A promising therapeutic strategy

Cited by 96 publications

References 75 publications

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

HIF-2α drives an intrinsic vulnerability to ferroptosis in clear cell renal cell carcinoma

Exploring the inhibition mechanism on HIF‐2 by inhibitor PT2399 and 0X3 using molecular dynamics simulations

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