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Ref Type Journal Article
PMID (27595393)
Authors Cho H, Du X, Rizzi JP, Liberzon E, Chakraborty AA, Gao W, Carvo I, Signoretti S, Bruick RK, Josey JA, Wallace EM, Kaelin WG
Title On-target efficacy of a HIF-2α antagonist in preclinical kidney cancer models.
Abstract Text Clear cell renal cell carcinoma, the most common form of kidney cancer, is usually linked to inactivation of the pVHL tumour suppressor protein and consequent accumulation of the HIF-2α transcription factor (also known as EPAS1). Here we show that a small molecule (PT2399) that directly inhibits HIF-2α causes tumour regression in preclinical mouse models of primary and metastatic pVHL-defective clear cell renal cell carcinoma in an on-target fashion. pVHL-defective clear cell renal cell carcinoma cell lines display unexpectedly variable sensitivity to PT2399, however, suggesting the need for predictive biomarkers to be developed to use this approach optimally in the clinic.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
PT2399 PT2399 2 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
PT2399 HIF2A Inhibitor 6 PT2399 is a small molecule that inhibits Hif2-alpha, resulting in decreased downstream signaling and potentially leading to reduced growth of tumors with defective VHL (PMID: 27595393, PMID: 30523118).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 R248W VHL inact mut clear cell renal cell carcinoma resistant PT2399 Preclinical - Cell culture Actionable In a preclinical study, TP53 R248W was associated with resistance to PT2399 in VHL-defective clear cell renal cell carcinoma cell lines in culture (PMID: 27595393). 27595393
VHL inact mut clear cell renal cell carcinoma conflicting PT2399 Preclinical - Pdx Actionable In a preclinical study, PT2399 had variable impact on tumor growth in clear cell renal cell carcinoma (ccRCC) cell line and patient-derived xenograft (PDX) models with defective VHL, with decreased tumor growth in a VHL-defective ccRCC PDX model and some VHL-defective ccRCC cell line xenograft models, and no tumor suppression in other cell line xenograft models (PMID: 27595393). 27595393